Preparation method of benzene olefin compounds and olefin boronic acid reagent

Abstract

The present invention relates to the field of organic synthesis, and more particularly to a method for preparing a benzene olefin compound and an olefin boronic acid reagent. The method for preparing a benzene olefin compound of the present invention comprises the following reaction formula: #imgabs0# wherein X1 and X2 are independently selected from chlorine, bromine or iodine, R1 is selected from a C2-C5 olefin group, and R a 、R b 、R c are independently selected from C1-C3 alkyl or R a 、R b 、R c Any two of them are bonded to form a ring, and R2 is selected from a C1-C6 alkyl group, comprising the following steps: (a) under the protection of an inert gas, mixing compound 1, compound 2 and a solvent, after which water and an alcohol are added to obtain a reaction solution; (b) mixing compound 3, a base, and a palladium catalyst with the reaction solution, pressurizing the reaction at a certain temperature for completion, and post-treating to obtain compound 4. Because the reaction system performs the coupling reaction under a certain temperature and pressure, the reaction can be carried out in a solvent-alcohol-water system with a relatively low boiling point (such as THF, diethyl ether, etc.) at normal pressure, so that the reaction conversion rate reaches 99%.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a preparation method of a benzene olefin compound and an olefin boronic acid reagent. Background Art

[0002] Styrene derivatives exhibit a strong AIE effect and high fluorescence quantum yields. They are also easily functionalized and synthesized, allowing for the design of highly selective fluorescent probes for specific ions, proteins, and other substances. They can also be used in the design of high-performance optical devices such as OLEDs. Some styrene derivatives exhibit good biocompatibility, excellent photostability, and high selectivity, making them promising for applications in medical and environmental fields such as cell imaging, drug delivery, and bacterial detection.

[0003] For example, Chinese patent CN 111499500A discloses a dopant polymer for fuel cells or conductive polymers. The patent indicates that various styrene compounds including 4-tert-butoxystyrene can be used as a monomer for preparing the polymer.

[0004] For example, Chinese patent CN 115894243A discloses a photoresist composition that can be used for photolithography in semiconductor chip technology. The patent indicates that 4-tert-butoxystyrene can be used as a monomer for preparing the polymer contained in the above composition.

[0005] In the prior art, A General Solution for Unstable Boronic Acids: Slow-Release Cross-Coupling from Air-Stable MIDA Borons (Journal of the American Chemical Society, 2009, vol. 131, p. 6961-6963) reports a method for preparing 4-tert-butoxystyrene, which uses 4-tert-butoxychlorobenzene and vinylboronic acid as reaction substrates, a mixed solution of dioxane and water as the reaction solvent, and a reaction temperature of 100° C. for 6 h, with a yield of 79%. The document also reports that when 6-methyl-2-vinyl-1,3,6,2-diol is used, When azaborane-4,8-dione is used as the reaction substrate instead of vinylboronic acid, the yield can be increased to 98%. However, the preparation of this reagent is complicated, it is not commercialized, and the production cost is too high.

[0006] In addition, it is worth noting that vinyl boronic acid is difficult to store for a long time. According to the literature mentioned above, after vinyl boronic acid was stored for 15 days and then reacted with 4-tert-butoxychlorobenzene under the same conditions, the yield was only 5%. Summary of the Invention

[0007] The present invention is made to solve the above problems, and its purpose is to provide a method for efficiently synthesizing benzene olefin compounds and an olefin boronic acid reagent that can maintain high reactivity after long-term storage.

[0008] One aspect of the present invention provides a method for preparing a benzene olefin compound, and the reaction formula is as follows:

[0009]

[0010] In the formula, X1 and X2 are independently selected from any one of chlorine, bromine or iodine,

[0011] R1 is selected from C2-C5 olefin groups,

[0012] R a 、R b 、R c are independently selected from C1-C3 alkyl or R a 、R b 、R c Any two of them are bonded into a ring,

[0013] R2 is selected from C1-C6 alkyl,

[0014] The preparation method comprises the following steps:

[0015] (a) Under the protection of inert gas, compound 1, compound 2 and a solvent are mixed and reacted completely, and then water and alcohol are added to obtain a reaction solution.

[0016] (b) Compound 3, a base, a palladium catalyst and the reaction solution are mixed, and after the pressure reaction is complete at a certain temperature, post-processing is performed to obtain compound 4.

[0017] Wherein, in the step (b), the reaction temperature is 70°C-120°C, and the pressure is increased to 0.11-0.15 MPa.

[0018] Another aspect of the present invention provides an olefin boronic acid reagent, which is prepared by the following method:

[0019] Under inert gas protection, compound 1 Compound 2 Lithium salt and solvent are mixed, and after the reaction is complete, water and alcohol are added to obtain olefin boronic acid reagent.

[0020] Wherein, R1 in Formula 1 is selected from a C2-C5 olefin group, X1 is selected from any one of chlorine, bromine or iodine, and R a 、R b 、R c are independently selected from C1-C3 alkyl or Ra 、R b 、R c Any two of them are bonded into a ring,

[0021] The lithium salt is lithium halide.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] According to the preparation method of benzene olefin compounds involved in the present application, because the reaction system carries out the coupling reaction under a certain temperature and pressure, the reaction can be carried out in a solvent (such as THF, diethyl ether, etc.)-alcohol (such as ethanol)-water system with a relatively low boiling point at normal pressure, so that the reaction conversion rate reaches 99%.

[0024] According to the olefin boronic acid reagent involved in the present application, since lithium salt is added, the lithium salt can make the prepared olefin boronic acid reagent more stable, so the olefin boronic acid reagent can still maintain high reactivity after long-term storage. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The product of Example 1 of the present invention 1 HNMR spectrum;

[0026] Figure 2 It is the GC chart of the product in Example 1 of the present invention. DETAILED DESCRIPTION

[0027] Hereinafter, the specific disclosed methods for preparing benzene olefin compounds and embodiments of olefin boronic acid reagents are described in detail.

[0028] Definition of terms

[0029] Unless otherwise specified, the following words, phrases and symbols used in this specification generally have the meanings described below.

[0030] In general, the nomenclature used herein (e.g., IUPAC nomenclature) and the laboratory procedures described below (including for cell culture, organic chemistry, analytical chemistry, and pharmacology, etc.) are those well known and commonly used in the art. Unless otherwise defined, all scientific and technical terms used herein in conjunction with the present disclosure described herein have the same meaning as commonly understood by those skilled in the art. Additionally, in the claims and / or the specification, when the term "one" or "an" is used in conjunction with the term "comprising" or a noun, its meaning may be "one", but is also consistent with the meaning of "one or more", "at least one", and "one or more than one". Similarly, the term "another" or "other" may mean at least a second or more.

[0031] It should be understood that whenever various aspects are described herein using the terms "including" or "comprising," other similar aspects described by "consisting of" and / or "consisting essentially of" are also provided.

[0032] As used herein, the term "alkyl" used alone or in combination may be straight-chain or branched, and the number of carbon atoms may be, for example, C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2. For example, alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and the like.

[0033] As used herein, the term "alkene group" alone or in combination includes straight-chain or branched alkene groups, and the number of carbon atoms thereof can be, for example, C2-C5, C2-C4, C2-C3, etc. For example, alkene groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, etc.

[0034] As used herein, the term "halogen," alone or in combination, refers to fluorine, chlorine, bromine or iodine.

[0035] Herein, bonding to form a ring means forming an aliphatic hydrocarbon ring, an aromatic hydrocarbon ring, an aliphatic heterocycle, an aromatic heterocycle, or a condensed ring thereof.

[0036] Preparation method of benzene olefin compounds

[0037] The present invention provides a method for preparing a benzene olefin compound, and the reaction formula is as follows:

[0038]

[0039] In the formula, X1 and X2 are independently selected from any one of chlorine, bromine or iodine,

[0040] R1 is selected from C2-C5 olefin groups,

[0041] R a 、R b 、R c are independently selected from C1-C3 alkyl or R a 、R b 、R c Any two of them are bonded into a ring,

[0042] R2 is selected from C1-C6 alkyl,

[0043] The preparation method comprises the following steps:

[0044] (a) Under the protection of inert gas, compound 1, compound 2 and a solvent are mixed and reacted completely, and then water and alcohol are added to obtain a reaction solution.

[0045] (b) Compound 3, a base, and a palladium catalyst are mixed with the reaction solution, and after the pressure reaction is complete at a certain temperature, post-processing is performed to obtain compound 4.

[0046] Wherein, in the step (b), the reaction temperature is 70° C.-120° C., and the pressure is increased to 0.11 MPa-0.15 MPa.

[0047] The method for preparing phenylene olefin compounds provided by the present invention may also have the following feature: wherein, the temperature of the mixed reaction of compound 1, compound 2, and solvent in step (a) is -5°C-15°C. In a specific embodiment, the temperature of the mixed reaction of compound 1, compound 2, and solvent in step (a) is -5°C-10°C, 10°C-15°C, -5°C-0°C, 0°C-5°C, or 5°C-10°C, etc. Preferably, it is -5°C-10°C.

[0048] The method for preparing benzene olefin compounds provided by the present invention may also have the following feature: lithium salt is further added in step (a).

[0049] The method for preparing phenylene olefin compounds provided by the present invention may also have the following feature: wherein the lithium salt is a lithium halide. In a specific embodiment, the lithium halide may be, for example, lithium bromide, lithium chloride, or the like.

[0050] The method for preparing benzene olefin compounds provided by the present invention may also have the following feature: wherein the molar ratio of the lithium salt to the compound 3 is (0.05-0.2): 1. In specific embodiments, the molar ratio of the lithium salt to the compound 3 may be, for example, (0.05-0.1): 1, (0.1-0.15): 1, or (0.15-0.2): 1.

[0051] The method for preparing benzene olefin compounds provided by the present invention may also have the following characteristics: wherein, in step (a), the solvent is selected from any one of tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, and diethyl ether.

[0052] The method for preparing benzene olefin compounds provided by the present invention may also have the following feature: wherein, in step (a), the inert gas is nitrogen or argon.

[0053] The method for preparing benzene olefin compounds provided by the present invention may also have the following feature: wherein, in step (a), the alcohol is selected from methanol or ethanol.

[0054] The method for preparing phenylene olefin compounds provided by the present invention may also have the following feature: wherein, in step (a), the volume ratio of water to alcohol is 1:(1-3), preferably 1:(1.5-2.5). In a specific embodiment, for example, when the alcohol is ethanol, the volume ratio of water to ethanol is 1:(1-3), preferably 1:(1.5-2.5).

[0055] The method for preparing benzene olefin compounds provided by the present invention may also have the following characteristics: wherein, in step (a), the molar ratio of compound 1 to compound 2 is 1-2:1-2.

[0056] The method for preparing benzene olefin compounds provided by the present invention may also have the following characteristics: wherein, in step (b), the base is selected from any one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium phosphate, and potassium phosphate.

[0057] In the preparation method of the benzene olefin compound provided by the present invention, it can also have such a feature: wherein, in step (b), the palladium catalyst is a palladium salt or a palladium salt / ligand. Optionally, the palladium salt is selected from any one or more of palladium dichloride, dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II), tris(dibenzylideneacetone)dipalladium, and dichlorobis(triphenylphosphine)palladium (II). The ligand is selected from any one or more of 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl, 1,2,3,4,5-pentylphenyl-1'-(di-tert-butylphosphino)ferrocene or triphenylphosphine. When using palladium salt / ligand as a catalyst, the molar ratio of palladium salt to ligand is 1:(1-3), preferably 1:(1.5-2.5). In a specific embodiment, for example, when the palladium catalyst is tris(dibenzylideneacetone)dipalladium, it can be used together with a ligand, and the ligand can be, for example, 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl, 1,2,3,4,5-pentylphenyl-1'-(di-tert-butylphosphino)ferrocene, etc.

[0058] The method for preparing benzene olefin compounds provided by the present invention may also have the following characteristics: wherein, in step (b), the post-treatment comprises at least the following steps: before quenching the reaction, first distilling off the solvent.

[0059] The preparation method of benzene olefin compounds provided by the present invention may also have the following characteristics: wherein, in step (b), the post-treatment comprises the following steps: distilling off the solvent, adding water, extracting, concentrating the organic phase, and distilling.

[0060] The method for preparing benzene olefin compounds provided by the present invention may also have the following characteristics: wherein, in step (b), the reaction temperature may be, for example, 70°C-90°C, 90°C-120°C, 70°C-80°C, 80°C-90°C, 90°C-100°C, 100°C-110°C or 110°C-120°C, etc.

[0061] The method for preparing benzene olefin compounds provided by the present invention may also have the following characteristics: wherein, in step (b), the pressure may be increased to, for example, 0.11MPa-0.12MPa, 0.12MPa-0.13MPa, 0.13MPa-0.14MPa or 0.14MPa-0.15MPa, etc.

[0062] The method for preparing benzene olefin compounds provided by the present invention may also have the following characteristics: wherein the molar ratio of compound 3, base and palladium catalyst is 1:(1-3):(0.001-0.05).

[0063] The method for preparing a benzene olefin compound provided by the present invention may also have the following characteristics: wherein R1 is selected from a C2-C5 olefin group, and optionally, R1 is selected from a C2-C4 or C2-C3 olefin group. In a specific embodiment, R1 is selected from ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, etc.

[0064] The preparation method of the benzene olefin compound provided by the present invention may also have the following characteristics: wherein R a 、R b 、R c are independently selected from C1-C3 alkyl groups. a 、R b 、R c are independently selected from methyl, ethyl, etc.

[0065] The preparation method of the benzene olefin compound provided by the present invention may also have the following characteristics: wherein R a 、R b 、R c Any two of them are bonded to form a ring, such as compound 2 can be

[0066] The method for preparing a benzene olefin compound provided by the present invention may also have the following characteristics: wherein R2 is selected from a C1-C6 alkyl group. Alternatively, R2 is selected from a C1-C5 alkyl group, a C1-C4 alkyl group, or a C1-C3 alkyl group. In a specific embodiment, R2 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, or a sec-butyl group.

[0067] In the preparation method of benzene olefin compounds provided by the present invention, compound 4 can be selected from 4-tert-butoxystyrene and the like.

[0068] Olefin boronic acid reagents

[0069] The present invention also provides an olefin boronic acid reagent having the following characteristics, which is prepared by the following method:

[0070] Under inert gas protection, compound 1 Compound 2 Lithium salt and solvent are mixed, and after the reaction is complete, water and alcohol are added to obtain olefin boronic acid reagent.

[0071] Wherein, R1 in Formula 1 is selected from a C2-C5 olefin group, X1 is selected from any one of chlorine, bromine or iodine, and R a 、R b 、R c are independently selected from C1-C3 alkyl or R a 、R b 、R c Any two of them are bonded into a ring,

[0072] The lithium salt is lithium halide.

[0073] The olefin boronic acid reagent provided by the present invention may also have the following characteristics: wherein R1 is selected from a C2-C5 olefin group, optionally, R1 is selected from a C2-C4 or C2-C3 olefin group. In specific embodiments, R1 is selected from ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, etc.

[0074] The olefin boronic acid reagent provided by the present invention may also have the following characteristics: wherein R a 、R b 、R c are independently selected from C1-C3 alkyl groups. a 、R b 、R c are independently selected from methyl, ethyl, etc.

[0075] The olefin boronic acid reagent provided by the present invention may also have the following characteristics: wherein R a 、R b 、R c Any two of them are bonded to form a ring, such as compound 2 can be

[0076] The olefin boronic acid reagent provided by the present invention may also have the following characteristics: wherein the lithium halide may be, for example, lithium bromide, lithium chloride, or the like.

[0077] The olefin boronic acid reagent provided by the present invention may also have the following characteristics: wherein the solvent is selected from any one of tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, and diethyl ether.

[0078] The olefin boronic acid reagent provided by the present invention may also have the following feature: wherein the inert gas is nitrogen or argon.

[0079] The olefin boronic acid reagent provided by the present invention may also have the following characteristics: wherein the reaction temperature is controlled to be -5°C-15°C. In specific embodiments, the reaction temperature is controlled to be -5°C-10°C, 10°C-15°C, 0°C-5°C, or 5°C-10°C, etc. Preferably, it is -5°C-10°C.

[0080] The olefin boronic acid reagent provided by the present invention may also have the following characteristics: wherein the alcohol is selected from methanol or ethanol.

[0081] The olefin boronic acid reagent provided by the present invention may also have the following characteristics: wherein the volume ratio of water to ethanol is 1:(1-3), preferably 1:(1.5-2.5).

[0082] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is described in detail below with reference to embodiments and drawings.

[0083] In the following examples, unless otherwise specified, all reaction raw materials are commercially available products.

[0084] In the following examples, the Pd-132 catalyst is dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II), CAS number: 887919-35-9; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium, CAS number: 60748-47-2; S-Phos is 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl, CAS number: 657408-07-6; Q-Phos is 1,2,3,4,5-pentylphenyl-1'-(di-tert-butylphosphino)ferrocene, CAS number: 312959-24-3; PdCl2(PPh3)2 is dichlorobis(triphenylphosphine)palladium (II), CAS number: 13965-03-2.

[0085] In the following examples, hr means hours.

[0086] In the following examples of the present invention, the yield is calculated as follows: yield = (mass of actual product / mass of theoretical product) * 100%.

[0087] <Example 1>

[0088] Preparation of compound 4a

[0089] This example provides a method for preparing compound 4a, and the reaction formula is as follows:

[0090]

[0091] The steps include:

[0092] In a four-necked flask, under nitrogen, 14.4 g of trimethyl borate (0.14 mol, 1.3 eq), 29 mL of THF (2 V / W), and a catalyst of LiCl (0.45 g, 0.01 mol, 0.1 eq) were added dropwise over 1 hour with stirring and temperature control at T1 of 0-5°C. After addition, 133 mL of vinyl magnesium chloride solution (1 M, 0.133 mol, 1.25 eq) was added dropwise with temperature control at 0-5°C. After addition, the temperature was raised and stirred at 40-50°C for 2 hours. After cooling to 10-15°C, 5.4 mL of water and 12 mL of ethanol were added dropwise. An exotherm occurred, and the reaction solution gradually became a substantially transparent, dissolved boric acid solution. Afterwards, 120 g of water, 22.0 g of K2CO3 (0.16 mol, 1.5 eq), 24.4 g of 4-tert-butoxybromobenzene (0.107 mol, 1.0 eq), and 0.37 g of Pd-132 catalyst (0.5 mmol, 0.005 eq) were added in sequence. After nitrogen replacement, the temperature was raised to T2 90°C in a sealed container, and nitrogen was introduced to make the pressure in the four-necked flask 0.11 MPa. The reaction was carried out for 10 hours. The sampling was controlled and the raw materials disappeared. The reaction system was distilled at 50°C until the system became viscous. 120 g of water was added, 56 g of n-heptane was added, and the reaction was carried out. The organic phase was taken and concentrated under reduced pressure to obtain 19.1 g of a crude product. The crude product was distilled under reduced pressure and the 82°C fraction (vacuum 0.1 mmHg) was taken to obtain 17.8 g of 4-tert-butoxystyrene, with a yield of 94.4% and a GC purity of 99.8%. The yield is calculated based on compound 3a. The theoretical amount of the product in this example is 0.107 mol. The yield of compound 4a = [17.8 / (0.107 * 176.26)] * 100% = 94.4%. The yield calculation method for other examples refers to Example 1.

[0093] Product 1 HNMR spectrum Figure 1 shown.

[0094] The GC chart of the product is as follows Figure 2 shown.

[0095] <Example 2>

[0096] Stress screening

[0097] Based on Example 1, this example screened the pressure of the reactor. Except for the parameters listed in the table below, the remaining steps were the same as those described in Example 1.

[0098] The screening results are shown in Table 1.

[0099] Table 1 Screening of reaction system pressure

[0100] Serial number Pressure (MPa) Isolation yield (%) 1 0.11 94.4 2 0.10 55.0 3 0.15 94.8

[0101] As shown in the table above, through the experiments described in this example, the applicant unexpectedly discovered that the reaction yield can be significantly improved by applying a certain pressure (for example, a pressure of 0.11 MPa-0.15 MPa) to the reaction system.

[0102] The applicant believes that this may be because the solvent system of the reaction involved in this embodiment is a THF-ethanol-water system, wherein tetrahydrofuran and ethanol have boiling points of 66°C and 78°C, respectively, at normal pressure. Under normal pressure, both will be vaporized into gas at a reaction temperature of 90°C, making it difficult for the reaction to proceed smoothly.

[0103] <Example 3>

[0104] Screening of reaction temperature T2

[0105] Based on Example 1, this example screened the reaction temperature T2 for preparing 4-tert-butoxystyrene. Except for the parameters listed in the table below, the remaining steps were the same as those described in Example 1.

[0106] The screening results are shown in Table 2.

[0107] Table 2 Screening of reaction temperature T2

[0108]

[0109]

[0110] As shown in Table 2, the separation yield is higher when the reaction temperature is 90°C, while the separation yield is lower when the reaction temperature is below 70°C. However, at 90°C, the reaction solvent system THF-ethanol-water system will be vaporized into gas, and the reaction is difficult to proceed smoothly. Therefore, by pressurizing the reaction solvent system, the boiling point can be increased to achieve a higher yield.

[0111] <Example 4>

[0112] Screening of palladium catalysts

[0113] In this example, palladium catalysts were screened on the basis of Example 1. Except for the parameters listed in the table below, the remaining steps were the same as those described in Example 1.

[0114] The screening results are shown in Table 3.

[0115] Table 3 Screening of palladium catalyst

[0116]

[0117] The amount of palladium catalyst mentioned in the above table is shown in Table 4:

[0118] Table 4 The amount of palladium catalyst

[0119]

[0120]

[0121] As shown in Table 3, when the palladium catalyst is Pd-132, Pd2(dba)3 / S-phos, Pd2(dba)3 / Q-phos, or PdCl2(PPh3)2, the reaction can be basically completed.

[0122] <Example 5>

[0123] Screening of reaction temperature T1

[0124] In this example, based on Example 1, the reaction temperature T1 for preparing vinylboronic acid was screened. Except for the parameters listed in the table below, the remaining steps were the same as those described in Example 1.

[0125] The screening results are shown in Table 5.

[0126] Table 5 Screening of reaction temperature T1

[0127] Serial number Temperature (℃) Isolation yield (%) 1 -5-0 94.8 2 0-5 94.4 3 10-15 92.2 4 40-45 35.1

[0128] As shown in Table 5, when the reaction temperature for preparing vinylboronic acid is 40°C, the separation yield is only 35%. When the reaction temperature is between -5°C and 15°C, the activity of the obtained boric acid solution is very high, and a higher separation yield can be achieved.

[0129] <Example 6>

[0130] Screening of boron reagents

[0131] In this example, boron reagents were screened, and the reaction formula is as follows:

[0132]

[0133] The steps include:

[0134] 120 g of water, 22.0 g of K2CO3 (0.16 mol, 1.5 eq), 24.4 g of 4-tert-butoxybromobenzene (0.107 mol, 1.0 eq), and 0.37 g of Pd-132 catalyst (0.5 mmol, 0.005 eq) were added to the boron reagent in sequence. After nitrogen replacement, the temperature was raised to 90°C in a sealed container with a nitrogen pressure of 0.11 MPa. The reaction was carried out for 10 hours. The reaction system was distilled at 50°C until the system became viscous. 120 g of water was added, 56 g of n-heptane was added, and the mixture was extracted. The organic phase was taken and concentrated under reduced pressure to obtain a crude product. The crude product was distilled under reduced pressure, and the 82°C fraction (vacuum 0.1 mmHg) was taken to obtain 4-tert-butoxystyrene.

[0135] Table 6 Screening of boron reagents

[0136] Serial number Boron reagent Isolation yield (%) 1 Boron Reagent A 94.4 2 Boron Reagent A-1 12.0 3 Boron reagent A-2 91.7 4 Boron reagent B 93.0 5 Boron reagent B-1 41.4 6 Boron reagent C 93.7 7 Boron Reagent C-1 92.5 8 Boron reagent D 36.0

[0137] The preparation methods of the boron reagents mentioned in Table 6 are as follows:

[0138] Boron Reagent A: In a four-necked flask under nitrogen, add 14.4 g of trimethyl borate (0.14 mol, 1.3 eq), 29 mL of THF (2 V / W), and LiCl (0.45 g, 0.01 mol, 0.1 eq) as a catalyst. Stir and control the temperature at 0-5°C. Add 133 mL of vinylmagnesium chloride solution (1 M, 0.133 mol, 1.25 eq) dropwise over 1 hour, controlling the temperature at 0-5°C. After addition, raise the temperature and control the temperature at 40-50°C, stirring for 2 hours. Lower the temperature to 10-15°C, add 5.4 mL of water and 12 mL of ethanol dropwise to obtain Boron Reagent A.

[0139] Boron reagent A-1: 100 mL of ethyl acetate was added to boron reagent A for extraction. The layers were separated due to solid interference. After standing for 2 hours, the upper organic phase was separated. The aqueous phase was extracted twice and then discarded. The organic phases were combined and concentrated to obtain an oil. The obtained extract was dissolved in 29 mL of THF, 5.4 mL of water, and 12 mL of ethanol to obtain boron reagent A-1.

[0140] Boron reagent A-2: Boron reagent A should be stored in the dark at 5°C for 30 days before use.

[0141] Boron Reagent B: In a four-necked flask under nitrogen, add 14.4 g of trimethyl borate (0.14 mol, 1.3 eq) and 29 mL of THF (2 v / w). Stir and control the temperature at 0-5°C. Add 133 mL of vinylmagnesium chloride solution (1 M, 0.133 mol, 1.25 eq) dropwise over 1 hour while controlling the temperature at 0-5°C. After addition, raise the temperature and control the temperature at 40-50°C while stirring for 2 hours. Lower the temperature to 10-15°C and add 5.4 mL of water and 12 mL of ethanol dropwise to obtain Boron Reagent B.

[0142] Boron reagent B-1: Boron reagent B should be stored in the dark at 5°C for 30 days before use.

[0143] Boron Reagent C: In a four-necked flask under nitrogen, add 14.4 g of trimethyl borate (0.14 mol, 1.3 eq), 29 mL of THF (2 v / w), and LiBr (0.87 g, 0.01 mol, 0.1 eq) as catalyst. Stir and control the temperature at 0-5°C. Add 133 mL of vinylmagnesium chloride solution (1 M, 0.133 mol, 1.25 eq) dropwise over 1 hour, controlling the temperature at 0-5°C. After addition, raise the temperature and control the temperature at 40-50°C, stirring for 2 hours. Cool the temperature to 10-15°C, add 5.4 mL of water and 12 mL of ethanol dropwise to obtain Boron Reagent C.

[0144] Boron reagent C-1: Boron reagent C should be stored in the dark at 5°C for 30 days before use.

[0145] Boron reagent D: Commercially available vinylboronic acid.

[0146] As shown in Table 6, the isolated yield of boron reagent A-1 in preparing 4-tert-butoxystyrene was only 12.0%. Therefore, the reactivity of the purified boron reagent was low, resulting in a very low yield.

[0147] The isolated yield of boron reagent A-2 for preparing 4-tert-butoxystyrene was 91.7%, while the isolated yields of boron reagent C and boron reagent C-1 were 93.7% and 92.5%, respectively. The boron reagent prepared after adding lithium salt and stored in the dark at 5°C for 30 days showed similar yields. Therefore, the boron reagent prepared in this application can maintain high reactivity after long-term storage.

[0148] The isolated yield of boron reagent B for preparing 4-tert-butoxystyrene was 93.0%, while the isolated yield of boron reagent B-1 was only 41.4%. Therefore, the effect of the boron reagent without lithium chloride after storage at 5°C in the dark for 30 days was poor.

[0149] The isolated yield of 4-tert-butoxystyrene prepared from boron reagent D is only 36.0%. Therefore, the vinylboronic acid currently available on the market cannot achieve a good reaction yield for the reaction of the present application.

[0150] <Example 7>

[0151] A preparation method of 4-tert-butoxystyrene

[0152] This comparative example provides a method for preparing 4-tert-butoxystyrene, and the reaction formula is as follows:

[0153]

[0154] The method comprises the following steps: placing 14.4 g of trimethyl borate (0.14 mol, 1.3 eq), 29 mL of THF (2 V / W), and a catalyst of LiCl (0.45 g, 0.01 mol, 0.1 eq) into a four-necked flask under nitrogen protection, stirring and controlling the temperature T1 at 0-5°C, adding dropwise 133 mL of vinyl magnesium chloride solution (1 M, 0.133 mol, 1.25 eq) over 1 hour, controlling the temperature at 0-5°C, raising the temperature after addition and controlling the temperature at 40-50°C, and stirring for 2 hours. Then, lowering the temperature to 10-15°C, adding dropwise 5.4 mL of water and 12 mL of ethanol, exothermic reaction occurs, and the reaction solution gradually becomes a substantially transparent, dissolved boric acid solution. Afterwards, 120 g of water, 22.0 g of K2CO3 (0.16 mol, 1.5 eq), 24.4 g of 4-tert-butoxybromobenzene (0.107 mol, 1.0 eq), and 0.37 g of Pd-132 catalyst (0.5 mmol, 0.005 eq) were added in sequence. After nitrogen replacement, the temperature was raised to 90°C in a sealed container, and the nitrogen pressure applied was 0.11 MPa. The reaction was carried out for 10 hours. After the reaction was completed, 500 mL of water was added, the layers were separated, and the organic phase was concentrated to obtain 22.1 g of a crude product with a conversion rate of 99.7%. The product was distilled under reduced pressure to obtain 12.5 g of pure 4-tert-butoxystyrene with a yield of 66.0% and a GC purity of 99%.

[0155] In this embodiment, compared with Example 1, after the reaction, the solvent was not distilled under reduced pressure first, but water was directly added to quench the reaction.

[0156] Since the reaction solvent system of this embodiment consists of THF, ethanol and water, on the one hand, a portion of the product will enter the aqueous phase with the ethanol, resulting in product loss. On the other hand, a portion of the inorganic salts will enter the organic phase with the ethanol and further enter the crude product. These inorganic salts will induce dimerization of the target product during the distillation of the crude product, further resulting in a decrease in yield.

[0157] Functions and Effects of the Embodiments

[0158] According to the preparation method of benzene olefin compounds involved in the above embodiment, because the reaction system is reacted at 0.11MPa-0.15MPa, the boiling point of the reaction solvent system is increased, so a higher reaction conversion rate can be achieved and the separation yield of the product can be improved.

[0159] Because when preparing 4-tert-butoxystyrene, a higher separation yield can be achieved when the reaction temperature is controlled at 90°C, while the reaction separation yield is lower when the temperature is lower than 70°C, it is necessary to pressurize this reaction system to increase the boiling point of the THF-ethanol-water system so that it will not vaporize at higher temperatures.

[0160] Because Pd-132, Pd2(dba)3 / S-phos, and Pd2(dba)3 / Q-phos palladium catalysts are selected, the yield of both brominated substrates and chloro substrates can reach over 94%.

[0161] When preparing vinylboronic acid, the reaction temperature is controlled to be -5°C to 15°C, preferably -5°C to 10°C, so that the activity of the boric acid solution is very high, thereby improving the separation yield of the reaction.

[0162] Because vinyl boronic acid is not purified after preparation, traditional extraction and purification can only cause the loss of vinyl boronic acid and reduce the purity of vinyl boronic acid, and it is directly put into the next reaction, so the reaction activity of the boric acid solution is higher, thereby improving the reaction separation yield.

[0163] Because the solvent is first distilled under reduced pressure in the post-treatment, it can not only recover the solvent, but also make the product completely insoluble in the brine phase, making the subsequent extraction highly selective, so the conversion rate of the reaction can be improved.

[0164] The above embodiments are preferred examples of the present invention and are not intended to limit the scope of protection of the present invention.

[0165] The applicant declares that while the above-described embodiments illustrate the methods for preparing phenyl olefin compounds and olefin boronic acid reagents, the present invention is not limited to these embodiments, and does not necessarily rely on these embodiments for implementation. Those skilled in the art will appreciate that any improvements to the present invention, equivalent substitutions for raw materials in the products of the present invention, addition of auxiliary components, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

[0166] The above embodiments are preferred examples of the present invention and are not intended to limit the scope of protection of the present invention. However, the present invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present invention, various simple variations of the technical solution of the present invention can be made, and these simple variations all fall within the scope of protection of the present invention.

[0167] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A method for preparing a benzene olefin compound, characterized in that: The reaction formula is as follows: In the formula, X1 and X2 are independently selected from any one of chlorine, bromine or iodine, R1 is selected from C2-C5 olefin groups, R a 、R b 、R c independently selected from C1-C3 alkyl groups, R2 is selected from C1-C6 alkyl, The preparation method comprises the following steps: (a) Under the protection of inert gas, compound 1, compound 2, lithium salt and solvent are mixed and reacted completely, and then water and alcohol are added to obtain a reaction solution. (b) Compound 3, a base, and a palladium catalyst are mixed with the reaction solution, and after the pressure reaction is complete at a certain temperature, post-processing is performed to obtain compound 4. Wherein, in step (a), the solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran; In step (a), the lithium salt is lithium halide; In step (a), the alcohol is selected from methanol or ethanol; In step (b), the reaction temperature is 70° C.-120° C., and the pressure is increased to 0.11 MPa-0.15 MPa.

2. The method for preparing a benzene olefin compound according to claim 1, wherein: In step (a), the mixed reaction temperature of compound 1, compound 2 and solvent is -5°C to 15°C.

3. The method for preparing a benzene olefin compound according to claim 1, wherein: The molar ratio of the lithium salt to the compound 3 is (0.05-0.2):

1.

4. The method for preparing a benzene olefin compound according to claim 1, wherein: In step (a), the inert gas is nitrogen or argon.

5. The method for preparing a benzene olefin compound according to claim 1, wherein: In step (b), the base is selected from any one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium phosphate and potassium phosphate.

6. The method for preparing a benzene olefin compound according to claim 1, wherein: In step (b), the palladium catalyst is a palladium salt or a palladium salt / ligand, The palladium salt is selected from any one or more of palladium dichloride, dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II), tris(dibenzylideneacetone)dipalladium, and dichlorobis(triphenylphosphine)palladium (II). The ligand is selected from any one or more of 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl, 1,2,3,4,5-pentylphenyl-1'-(di-tert-butylphosphino)ferrocene or triphenylphosphine.

7. The method for preparing a benzene olefin compound according to claim 1, wherein: In step (b), the post-treatment comprises at least the following steps: before quenching the reaction, first distilling off the solvent.

8. The method for preparing a benzene olefin compound according to claim 7, wherein: The post-treatment comprises the following steps: removing the solvent by distillation, adding water, extracting, concentrating the organic phase, and distilling.

9. An olefin boronic acid reagent, characterized in that Prepared by the following method: Under inert gas protection, compound 1 Compound 2 Lithium salt and solvent are mixed, and after the reaction is complete, water and alcohol are added to obtain olefin boronic acid reagent. Wherein, in formula 1, R1 is selected from C2-C5 olefin groups, X1 is selected from any one of chlorine, bromine or iodine, In formula 2, R a 、R b 、R c independently selected from C1-C3 alkyl groups, The lithium salt is lithium halide; The solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran; The alcohol is selected from methanol or ethanol.

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