A synthetic method of α-halogenated borate compound and its product

Abstract

The invention discloses a method for synthesizing α-halogenated borate compounds and products thereof, method: in an atmosphere of inert gas, after a catalyst, a ligand, a base and a boronating agent are dissolved in an organic solvent, an aldehyde or ketone compound (I) is added to react, and the structural formula of the aldehyde or ketone compound (I) is as follows: wherein R1 and R2 are hydrogen atoms, aryl groups, alkyl groups or substituted alkyl groups, R1 and R2 are directly connected to form a closed-loop structure or are not directly connected to form an open-loop structure, and Y is CH2, O, S, NH and its corresponding structure with a substituent; after cooling and concentrating, dissolving, adding a halogenating agent to carry out a halogenation reaction, and then concentrating and purifying to separate, an α-halogenated borate compound is obtained. The present invention constructs a secondary or tertiary α-halogenated borate compound from aldehyde and ketone compounds by copper-catalyzed halogenated boronation reaction; the synthetic method has mild conditions, simple steps and low cost.

Description

Technical Field

[0001] The invention relates to the technical field of halogenated borate compounds and synthesis thereof, in particular to a synthesis method of α-halogenated borate compounds and products thereof, and in particular to a synthesis method of a class of novel α-halogenated borate compounds and chiral α-chloroborate compounds and products thereof. Background Art

[0002] Organoboron compounds play a very important role in modern organic chemistry. As extremely important synthons, they can undergo a variety of transformations. In recent years, organoboron has appeared more and more frequently in functional molecules (including drug molecules). α-Halogenated borate compounds, as a special type of amphiphilic compounds containing both nucleophilic carbon-boron bonds and electrophilic carbon-halogen bonds, have important application value in organic synthesis and drug synthesis.

[0003] Existing methods for synthesizing α-haloborate compounds often require very strong bases, extremely low temperatures, and organometallic reagents that are sensitive to air and moisture, resulting in many functional groups being incompatible in the methods, and existing synthetic methods are limited to secondary α-haloborate compounds.

[0004] Therefore, it is of great practical significance to develop a synthetic method for α-haloborate compounds with mild synthesis conditions and relatively simple steps. Summary of the invention

[0005] Since the prior art has the defect of harsh synthesis conditions for α-haloborate compounds, the present invention provides a method for synthesizing α-haloborate compounds with mild synthesis conditions and relatively simple steps. The present invention is not only suitable for synthesizing secondary α-haloborate compounds, but also reports tertiary α-haloborate compounds for the first time, and also provides a method for synthesizing such new compounds, and also provides technical support for them as reagents, ligands, catalysts, etc.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] A method for synthesizing an α-halogenated borate ester compound, the steps of which are as follows:

[0008] (1) Under an inert gas atmosphere, a catalyst, a ligand, a base and a boronating agent are dissolved in an organic solvent, and then an aldehyde or ketone compound (I) is added for reaction. The structural formula of the aldehyde or ketone compound (I) is as follows:

[0009]

[0010] Wherein R1 and R2 are hydrogen atoms, aryl groups, alkyl groups or substituted alkyl groups, R1 and R2 are directly connected to form a closed ring structure or are not directly connected to form an open ring structure, Y is CH2, O, S, NH and corresponding structures with substituents, the number of carbon atoms in the closed ring structure containing Y is not limited and other positions on the closed ring except the α position may also be grafted with other groups, and those skilled in the art may adjust according to actual conditions;

[0011] (2) cooling and concentrating, dissolving, adding a halogenating agent to carry out a halogenation reaction, and then concentrating, purifying and separating to obtain an α-halogenated borate ester compound.

[0012] The present invention realizes the synthesis of α-haloborate and chiral α-chloroborate compounds by deoxyhaloboration of aldehydes or ketones. The method has many advantages such as high reaction efficiency, mild reaction, good atom economy, excellent functional group compatibility and substrate universality.

[0013] As the preferred technical solution:

[0014] In the synthesis method as described above, the inert gas is nitrogen, helium, neon or argon;

[0015] The organic solvent in step (1) is one or a mixture of two or more of benzene, toluene, xylene, trimethylbenzene, trifluorotoluene, chlorobenzene, ethylene glycol dimethyl ether, anisole, methyl tert-butyl ether, dichloromethane, dichloroethane, chloroform, ethyl acetate, 1,4-dioxane, ether, tetrahydrofuran, acetone, acetonitrile, n-hexane, cyclohexane, N,N'-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide;

[0016] The catalyst is one or a mixture of two or more of cupric acetate, cupric chloride, cuprous chloride, cuprous bromide, cuprous iodide, nickel bromide, nickel chloride, nickel iodide, ferric chloride, ferrous chloride, cobalt bromide and cobalt acetate;

[0017] The base is one or a mixture of two or more of cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium phosphate, lithium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, potassium methoxide, lithium methoxide, triethylamine, N,N,N',N'-tetramethylethylenediamine and tetramethylguanidine;

[0018] The boronization reagent is one or a mixture of two or more of the following: pinacol diborate, catechol diborate, neopentyl glycol diborate and 1-pinacol-2-(1,8)naphthalene diamine diborate;

[0019] The halogenating agent is one or a mixture of two or more of tert-butyldimethylsilyl chloride, triethylsilyl chloride, triisopropylsilyl chloride, trimethylsilyl chloride, tributylsilyl chloride, diphenylmethylsilyl chloride, dimethylphenylsilyl chloride, lithium chloride, tetrabutylammonium chloride, trimethylbromosilane, triethylbromosilane, sodium bromide, lithium bromide, tetrabutylammonium bromide, trimethylsilyl iodide, triethylsilyl iodide, sodium iodide, potassium iodide and tetrabutylammonium iodide;

[0020] The organic solvent used for the dissolution is one or a mixture of two or more of ethylene glycol dimethyl ether, ethylene dichloride, tetrahydrofuran, cyclohexane, 1,4-dioxane, toluene, acetonitrile, dimethyl sulfoxide, methyl tert-butyl ether, ether, acetone, methyl ethyl ketone, N,N'-dimethylformamide and N,N'-dimethylacetamide;

[0021] The amount of the base added is 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I);

[0022] The amount of the boronating agent added is 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I);

[0023] The amount of the halogenating agent added is 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I);

[0024] The reaction temperature of the reaction in step (1) is 0 to 150° C., and the reaction time is 1 to 48 hours;

[0025] The reaction temperature of the halogenation reaction is 0 to 150° C., and the reaction time is 1 to 48 hours;

[0026] The ligand is a monophosphine ligand, a diphosphine ligand, a nitrogen ligand or a carbene ligand, and the corresponding racemic ligand and chiral ligand can be used;

[0027] The added amount of the ligand is 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I).

[0028] In the above-mentioned synthesis method, the organic solvent in step (1) is toluene;

[0029] The catalyst is cuprous chloride;

[0030] The base is sodium tert-butoxide;

[0031] The boronation reagent is pinacol diboron;

[0032] The halogenating agent is one or a mixture of two or more of trimethylsilyl chloride, trimethylsilyl bromide and trimethylsilyl iodide;

[0033] The organic solvent used for the dissolution is acetone;

[0034] The amount of the base added is 10 to 100% molar equivalent of the aldehyde or ketone compound (I);

[0035] The amount of the boronating agent added is 110% molar equivalent of the aldehyde or ketone compound (I);

[0036] The amount of the halogenating agent added is 200 to 500% molar equivalent of the aldehyde or ketone compound (I);

[0037] The reaction temperature of the reaction in step (1) is 25 to 80° C., and the reaction time is 5 to 12 hours;

[0038] The reaction temperature of the halogenation reaction is room temperature and the reaction time is 12h;

[0039] The ligand is 1,3-di(1-adamantyl)imidazolinium tetrafluoroborate, 1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborate, 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride, 1,3-dicyclohexylimidazolium chloride, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), 1,3-bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane, Bis(2-(dicyclohexylphosphino)ethyl)amine, bis(2-diphenylphosphinophenyl)ether, 1,1'-bis(dicyclohexylphosphino)ferrocene, 2,2'-bis(dicyclohexylphosphino)-1,1'-biphenyl, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, (R)-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (R-BINAP), (S)-(-)-2,2'-bis[bis(3,5 -di-tert-butyl-4-methoxyphenyl)phosphine]-1,1'-binaphthyl (S-DTBM-BINAP), (R)-(+)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxole (R-SEGPHOS), (S)-(-)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxole (S-DM-SEGPHOS), (R)-(+)-2, 2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphine)-3,3'-bipyridine, (S)-(-)-2,2'-bis(di-p-tolylphosphine)-6,6'-dimethoxy-1,1'-biphenyl, (2S,4S)-(-)-2,4-bis(diphenylphosphine)pentane, one or a mixture of two or more of L1, L2, L3 and L4, wherein the structural formulas of L1, L2, L3 and L4 are respectively:

[0040]

[0041] The added amount of the ligand is 5-10% molar equivalent of the aldehyde or ketone compound (I).

[0042] In the synthesis method as described above, the ligand is one or a mixture of two or more of 1,3-dicyclohexyl imidazole chloride, L1 and L2.

[0043] In the above-mentioned synthesis method, an additive is further added in step (1). Whether the additive is added depends on whether the product is a chiral compound. The additive needs to be added to prepare a chiral compound, but no additive needs to be added to prepare a racemic structure.

[0044] The additive is one or a mixture of two or more of methanol, ethanol, tert-butyl alcohol, isopropanol, hexafluoroisopropanol, benzyl alcohol, ethylene glycol and glycerol;

[0045] The additive is added in an amount of 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I).

[0046] The synthetic method as described above, wherein the additive is methanol;

[0047] The additive is added in an amount of 150 to 500% molar equivalent of the aldehyde or ketone compound (I).

[0048] The present invention provides a product obtained by the above-mentioned synthesis method, wherein the product is a compound having a structure as shown in formula (II), formula (III) or formula (IV) or an enantiomer structure of a compound having a structure as shown in formula (III) and a racemic structure thereof;

[0049]

[0050] Wherein R1 and R2 are hydrogen atoms, aryl groups, alkyl groups or substituted alkyl groups, R1 and R2 are directly connected to form a closed ring structure or are not directly connected to form an open ring structure, Y is CH2, O, S, NH and its corresponding structure with substituents, X is Cl, Br or I, and the structural formula of BPin is as follows:

[0051]

[0052] As the preferred technical solution:

[0053] The product as described above, the specific structural formula of the product is:

[0054] or

[0055] The present invention also provides the use of the product as described above.

[0056] The above invention has the following advantages or beneficial effects:

[0057] The invention starts from readily available aldehyde and ketone compounds and constructs secondary and tertiary α-halogenated borate compounds and chiral α-chloroborate compounds through copper-catalyzed halogenated borate reaction. The method of the invention has mild synthesis conditions, relatively simple steps and relatively low cost, and has great application prospects. DETAILED DESCRIPTION

[0058] The present invention will be further described below in conjunction with specific embodiments, but they are not intended to limit the present invention.

[0059] The specific structural formulas of ligands L1, L2, L3, and L4 in the following examples are as follows:

[0060] Example 1

[0061] Synthesis of:

[0062] In a glove box, add pinacol diboron (0.1392 g, 0.55 mmol), NaOtBu (0.0048 g, 0.05 mmol), ICyCuCl (0.0083 g, 0.025 mmol), toluene (1.0 mL), (0.1515 g, 0.5 mmol). The Schlenk tube was sealed and removed from the glove box and stirred at 80 ° C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0 mL). Trimethylsilyl chloride (0.1086 g, 1.0 mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and obtain 0.1238 g of product. The yield was 55%.

[0063] 1H NMR (600MHz, CDCl3) δ7.99 (dd, J=7.8, 1.2Hz, 1H), 7.80 (dd, J=7.8, 1.8Hz, 1H), 7.41 (td, J=7.8, 1.2Hz, 1H ),7.16(dd,J=7.8,1.8Hz,1H),4.37(t,J=6.0Hz,2H),3.51-3.47(m,1H),2.07-1.91(m,2H),1.28(s,12H).

[0064] 13C NMR (151MHz, CDCl3) δ166.5,141.2,135.3,132.5,130.9,127.9,94.0,84.5,65.1,30.7,26.4,25.0,24.6,24.6.

[0065] HRMS:m / z(ESI)calculated[M+NH4]+:468.0604,found:468.0570.

[0066] Example 2

[0067] Synthesis of:

[0068] In a glove box, add pinacol diboronate (0.1392 g, 0.55 mmol), NaOtBu (0.0048 g, 0.05 mmol), ICyCuCl (0.0083 g, 0.025 mmol), toluene (1.0 mL), (0.1015 g, 0.5 mmol). The Schlenk tube was sealed and removed from the glove box and stirred at 80 ° C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0 mL). Trimethylsilyl bromide (0.1531 g, 1.0 mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and obtain 0.1474 g of product. The yield was 75%.

[0069] 1H NMR (600MHz, CDCl3) δ7.84 (dd, J=6.0, 3.6Hz, 2H), 7.72 (dd, J=5.4, 3.0Hz, 2H), 3.93-3.80 (m, 1H), 3.85-3 .80(m,1H),3.31(dd,J=9.0,6.6Hz,1H),2.36-2.29(m,1H),2.28-2.21(m,1H),1.29(s,6H),1.28(s,6H).

[0070] 13C NMR (151MHz, CDCl3) δ168.1,133.9,132.0,123.2,84.3,37.1,32.8,24.4,24.3.

[0071] HRMS:m / z(ESI)calculated[M+H]+:394.0823,found:394.0815.

[0072] Example 3

[0073] Synthesis of:

[0074] In a glove box, add pinacol diboronate (0.1392 g, 0.55 mmol), NaOtBu (0.0048 g, 0.05 mmol), ICyCuCl (0.0083 g, 0.025 mmol), toluene (1.0 mL), (0.0971 g, 0.5 mmol). The Schlenk tube was sealed and removed from the glove box and stirred at 80 ° C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0 mL). Trimethyl iodosilane (0.200 g, 1.0 mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and obtain 0.1339 g of product. The yield was 62%.

[0075] 1H NMR (600MHz, CDCl3) δ6.78(m,1H),6.73(m,2H),3.87(s,3H),3.84(s,3H),3.19(t,J=7.2Hz,1 H),2.75-2.65(m,1H),2.64-2.55(m,1H),2.20-2.11(m,1H),2.07-1.98(m,1H),1.27(s,12H).

[0076] 13C NMR (151MHz, CDCl3) δ148.7,147.2,133.2,120.3,111.8,111.2,83.8,55.8,36.6,36.3,24.3,24.1.

[0077] HRMS:m / z(ESI)calculated[M+Na]+:455.0864,found:455.0867.

[0078] Example 4

[0079] Synthesis of:

[0080] In a glove box, add pinacol diboronate (0.1392 g, 0.55 mmol), NaOtBu (0.0048 g, 0.05 mmol), ICyCuCl (0.0083 g, 0.025 mmol), toluene (1.0 mL), (0.0920 g, 0.5 mmol). The Schlenk tube was sealed and removed from the glove box and stirred at 80 ° C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0 mL). Trimethylsilyl chloride (0.1086 g, 1.0 mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and obtain 0.0809 g of product. The yield was 49%.

[0081] 1H NMR (400MHz, CDCl3) δ7.45 (d, J = 8.2Hz, 2H), 7.31 (d, J = 8.2Hz, 2H), 4.42 (s, 1H), 1.27 (s, 12H).

[0082] 13C NMR (101MHz, CDCl3) δ137.9,131.8,130.2,121.8,84.9,24.5.

[0083] MS:(EI)[M]+:329.95.

[0084] Example 5

[0085] Synthesis of:

[0086] In a glove box, add pinacol diboronate (0.1392 g, 0.55 mmol), NaOtBu (0.0048 g, 0.05 mmol), ICyCuCl (0.0083 g, 0.025 mmol), toluene (1.0 mL), (0.0681 g, 0.5 mmol). The Schlenk tube was sealed and removed from the glove box and stirred at 80°C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0 mL). Trimethylsilyl bromide (0.1531 g, 1.0 mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and 0.0554 g of product was obtained. The yield was 34%.

[0087] 1H NMR (400MHz, CDCl3) δ7.22(t,J=8.0Hz,1H),7.12-7.06(m,2H),6.85-6.77(m,1H),4.40(s,1H),3.81(s,3H),1.30(s,12H).

[0088] 13C NMR (101MHz, CDCl3) δ159.7,140.2,129.6,121.9,115.0,113.9,84.6,55.2,24.5,24.5.

[0089] MS:(EI)[M]+:326.00.

[0090] Example 6

[0091] Synthesis of:

[0092] In a glove box, add pinacol diboronate (0.1392 g, 0.55 mmol), NaOtBu (0.0048 g, 0.05 mmol), ICyCuCl (0.0083 g, 0.025 mmol), toluene (1.0 mL), (0.0800 g, 0.5 mmol). The Schlenk tube was sealed and removed from the glove box and stirred at 80 ° C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0 mL). Trimethyl iodosilane (0.200 g, 1.0 mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and obtain 0.1196 g of product. The yield was 60%.

[0093] 1H NMR (400MHz, CDCl3) δ6.63 (t, J = 8.8Hz, 2H), 4.75 (s, 1H), 1.29 (s, 12H).

[0094] 13C NMR (101MHz, CDCl3) δ164.1-158.8 (m), 115.9-114.5 (m), 100.6 (td, J = 26.4, 3.2Hz), 85.5, 24.6, 24.4.

[0095] HRMS:m / z(ESI)calculated[M+Na]+:421.0066,found:421.0056.

[0096] Example 7

[0097] Synthesis of:

[0098] In a glove box, add pinacol diboronate (1.3920 g, 5.5 mmol), NaOtBu (0.0480 g, 0.5 mmol), ICyCuCl (0.0830 g, 0.25 mmol), toluene (10.0 mL), (0.4200 g, 5.0 mmol). The Schlenk tube was sealed and moved out of the glove box and stirred at 80 ° C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (10.0 mL). Trimethylsilyl chloride (1.0860 g, 10.0 mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and 0.8500 g of product was obtained. The yield was 79%.

[0099] 1H NMR (600MHz, CDCl3) δ3.19 (d, J = 9.2Hz, 1H), 2.55 (m, 1H), 2.00-1.91 (m, 1H), 1.89-1.80 (m, 1H), 1.76-1.59 (m, 4H), 1.10 (s, 12H).

[0100] 13C NMR (151MHz, CDCl3) δ84.2, 38.6, 26.9, 25.8, 24.5, 24.5, 17.4.

[0101] MS:(EI)[M]+:230.00.

[0102] Example 8

[0103] Synthesis of:

[0104] In a glove box, add pinacol diboronate (0.1392 g, 0.55 mmol), NaOtBu (0.0048 g, 0.05 mmol), ICyCuCl (0.0083 g, 0.025 mmol), toluene (1.0 mL), (0.0561 g, 0.5 mmol). The Schlenk tube was sealed and removed from the glove box and stirred at 80°C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0 mL). Trimethylsilyl bromide (0.1531 g, 1.0 mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and 0.1000 g of the product was obtained. The yield was 66%.

[0105] 1H NMR (400MHz, CDCl3): δ3.12(d,J=8.8Hz,1H),2.09(d,J=13.1Hz,1H),1.80-1.58(m,6H),1.28(s,12H),1.76-1.05(m,4H)

[0106] 13C NMR (101MHz, CDCl3) δ84.1,40.7,32.2,31.7,26.2,26.2,26.0,24.5,24.4

[0107] HRMS:m / z(ESI)calculated[M+Na]+:324.0981found 324.0985.

[0108] Example 9

[0109] Synthesis of:

[0110] In a glove box, add pinacol diboronate (0.1392 g, 0.55 mmol), NaOtBu (0.0048 g, 0.05 mmol), ICyCuCl (0.0083 g, 0.025 mmol), toluene (1.0 mL), (0.0415 g, 0.5 mmol). The Schlenk tube was sealed and removed from the glove box and stirred at 80 ° C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0 mL). Trimethyl iodosilane (0.200 g, 1.0 mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and obtain 0.1139 g of product. The yield was 71%.

[0111] 1H NMR (600MHz, CDCl3) δ3.33 (dd, J = 9.0, 6.0Hz, 1H), 2.62-2.56 (m, 1H), 2.53-2.47 (m, 1H), 2.18-2.05 (m, 2H), 1.28 (s, 12H).

[0112] 13C NMR (151MHz, CDCl3) δ118.6,84.4,30.0,24.4,24.2,18.9.

[0113] HRMS:m / z(ESI)calculated[M+Na]+:344.0291,found:344.0279.

[0114] Example 10

[0115] Synthesis of:

[0116] In a glove box, add pinacol diboronate (1.3920 g, 5.5 mmol), NaOtBu (0.0480 g, 0.5 mmol), ICyCuCl (0.0830 g, 0.25 mmol), toluene (10.0 mL), (0.5000 g, 5.0 mmol). The Schlenk tube was sealed and removed from the glove box and stirred at 80 ° C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (10.0 mL). Trimethylsilyl chloride (1.0860 g, 10.0 mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and obtain 0.7011 g of product. The yield was 57%.

[0117] 1H NMR (600MHz, CDCl3) δ3.97-3.93(m,2H),3.54-3.49(m,2H),2.22-2.12(m,2H),1.95-1.90(m,2H),1.30(s,12H).

[0118] 13C NMR (151MHz, CDCl3) δ84.5, 65.2, 37.1, 24.5.

[0119] HRMS:m / z(ESI)calculated[M+Na]+:269.1088,found:269.1086.

[0120] Embodiment 11

[0121] Synthesis of:

[0122] In a glove box, add pinacol diboronate (0.1392 g, 0.55 mmol), NaOtBu (0.0048 g, 0.05 mmol), ICyCuCl (0.0083 g, 0.025 mmol), toluene (1.0 mL), (0.0861 g, 0.5 mmol). The Schlenk tube was sealed and removed from the glove box and stirred at 80°C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0 mL). Trimethylsilyl bromide (0.1531 g, 1.0 mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and obtain 0.0779 g of product. The yield was 43%.

[0123] 1H NMR (600MHz, CDCl3) δ4.19-4.11(m,2H),2.69-2.44(m,3H),1.56-1.46(m,3H),1.36-1.19(m,17H),0.90(t,J=7.2Hz,3H).

[0124] 13C NMR (151MHz, CDCl3) δ173.4,84.4,60.5,44.5,38.6,26.8,24.8,24.8,23.2,14.2,14.0.

[0125] MS:(EI)[M]+:362.10.

[0126] Example 12

[0127] Synthesis of:

[0128] In a glove box, add pinacol diboronate (0.1392 g, 0.55 mmol), NaOtBu (0.0048 g, 0.05 mmol), ICyCuCl (0.0083 g, 0.025 mmol), toluene (1.0 mL), (0.1060 g, 0.5 mmol). The Schlenk tube was sealed and removed from the glove box and stirred at 80 ° C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0 mL). Trimethyl iodosilane (0.200 g, 1.0 mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and obtain 0.1148 g of product. The yield was 51%.

[0129] 1H NMR (600MHz, CDCl3) δ7.57-7.53(m,2H),7.22(td,J=7.2,1.2Hz,1H),7.09(td,J=7.8,1.8Hz ,1H),3.74(d,J=13.8Hz,1H),3.63(d,J=13.8Hz,1H),1.92(s,3H),1.32(s,6H),1.29(s,6H).

[0130] 13C NMR (151MHz, CDCl3) δ139.3,133.0,131.3,128.3,127.1,125.8,84.3,47.7,28.0,24.4,24.3.

[0131] HRMS:m / z(ESI)calculated[M+H]+:450.9935,found:450.9916.

[0132] Embodiment 13

[0133] Synthesis of:

[0134] In a glove box, pinacol diboronate (0.0765 g, 0.28 mmol), KOtBu (0.0031 g, 0.05 mmol), CuCl (0.0025 g, 0.025 mmol), L1 (0.0295 g, 0.025 mmol), and toluene (0.5 mL) were added to a dry 25 mL Schleck tube, and the reaction mixture was stirred at room temperature for 30 minutes. Then, (0.0530g, 0.25mmol) and MeOH (0.38mmol). The Schlenk tube was sealed and moved out of the glove box and stirred at 80°C for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0mL). Trimethylsilyl chloride (0.0543g, 0.5mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and obtain 0.0448g of product. The yield was 50% and the er value was 97:3.

[0135] 1H NMR(600MHz, CDCl3) δ7.52(d,J=7.8Hz,1H),7.28-7.20(m,3H),7.06(t,J=7.8Hz,1H),3. 46-3.42(m,1H),3.02-2.97(m,1H),2.91-2.80(m,1H),2.18-2.06(m,2H),1.29(s,12H).

[0136] 13C NMR (151MHz, CDCl3) δ140.4,132.8,130.7,127.8,127.5,124.4,84.5,33.8,33.7,24.6,24.6.

[0137] MS:(EI)[M]+:358.00.

[0138] Embodiment 14

[0139] Synthesis of:

[0140] In a glove box, pinacol diboronate (0.0765 g, 0.28 mmol), KOtBu (0.0561 g, 0.5 mmol), CuCl (0.0025 g, 0.025 mmol), L2 (0.0127 g, 0.025 mmol), and toluene (1.0 mL) were added to a dry 25 mL Schleck tube, and the reaction mixture was stirred at room temperature for 30 minutes. Then, (0.0740g, 0.5mmol) and MeOH (1.0mmol). The Schlenk tube was sealed and moved out of the glove box and stirred at room temperature for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0mL). Trimethylchlorosilane (0.2716g, 2.5mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and obtain 0.0897g of product. The yield was 61% and the er value was 80:20.

[0141] 1H NMR (600MHz, CDCl3) δ7.31-7.24(m,2H),7.22-7.17(m,3H),2.80-2.70(m,2H),2.19-2.04(m,2H),1.63(s,3H),1.30(s,12H).

[0142] 13C NMR (151MHz, CDCl3) δ141.9,128.4,128.4,125.9,84.5,44.1,32.3,27.0,24.6,24.6.

[0143] MS:(EI)[M]+:294.05.

[0144] Embodiment 15

[0145] Synthesis of:

[0146] In a glove box, pinacol diboronate (0.0765 g, 0.28 mmol), KOtBu (0.0561 g, 0.5 mmol), CuCl (0.0025 g, 0.025 mmol), L2 (0.0127 g, 0.025 mmol), and toluene (1.0 mL) were added to a dry 25 mL Schleck tube, and the reaction mixture was stirred at room temperature for 30 minutes. (0.1030g, 0.5mmol) and MeOH (1.0mmol). The Schlenk tube was sealed and moved out of the glove box and stirred at room temperature for 12 hours. The reaction solution was cooled to room temperature and the solvent was concentrated in vacuo. The crude product was dissolved in acetone (1.0mL). Trimethylsilyl chloride (0.2716g, 2.5mmol) was added to the solution. After stirring at room temperature for 12 hours, the solvent was concentrated in vacuo. Column chromatography was used to separate and obtain 0.0615g of product. The yield was 41% and the er value was 83:17.

[0147] Those skilled in the art should understand that those skilled in the art can implement variations by combining the prior art and the above embodiments, which will not be described in detail here. Such variations do not affect the essential content of the present invention, and will not be described in detail here.

[0148] The above describes the preferred embodiments of the present invention. It should be understood that the present invention is not limited to the above-mentioned specific embodiments, and the devices and structures that are not described in detail should be understood to be implemented in a common manner in the art; any technician familiar with the art can use the above-disclosed methods and technical contents to make many possible changes and modifications to the technical solutions of the present invention without departing from the scope of the technical solutions of the present invention, or modify them into equivalent embodiments of equivalent changes, which does not affect the essential content of the present invention. Therefore, any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solutions of the present invention are still within the scope of protection of the technical solutions of the present invention.

Claims

1. A method for synthesizing an α-halogenated borate ester compound, characterized in that: The steps are as follows: (1) Under an inert gas atmosphere, a catalyst, a ligand, a base and a boronating agent are dissolved in an organic solvent, and then an aldehyde or ketone compound (I) is added for reaction. The structural formula of the aldehyde or ketone compound (I) is as follows: Wherein R1 and R2 are hydrogen atoms, aryl groups, alkyl groups or substituted alkyl groups, R1 and R2 are directly connected to form a closed ring structure or are not directly connected to form an open ring structure, and Y is CH2, O, S, NH and the corresponding structures with substituents; The catalyst is cuprous chloride, the ligand is a carbene ligand, the carbene ligand is 1,3-dicyclohexyl imidazole chloride, and the boronation reagent is biboric acid pinacol ester; (2) cooling and concentrating, dissolving, adding a halogenating agent to carry out a halogenation reaction, and then concentrating, purifying and separating to obtain an α-halogenated borate compound, wherein the halogenating agent is trimethylsilyl chloride, trimethylsilyl bromide or trimethylsilyl iodide; The α-halogenated borate compound is a compound having a structure as shown in formula (II) or formula (IV); Wherein R1 and R2 are hydrogen atoms, aryl groups, alkyl groups or substituted alkyl groups, R1 and R2 are directly connected to form a closed ring structure or are not directly connected to form an open ring structure, Y is CH2, O, S, NH and its corresponding structure with substituents, X is Cl, Br or I, and the structural formula of BPin is as follows:

2. The synthesis method according to claim 1, characterized in that The inert gas is nitrogen, helium, neon or argon; The organic solvent in step (1) is one or a mixture of two or more of benzene, toluene, xylene, trimethylbenzene, trifluorotoluene, chlorobenzene, ethylene glycol dimethyl ether, anisole, methyl tert-butyl ether, dichloromethane, dichloroethane, chloroform, ethyl acetate, 1,4-dioxane, ether, tetrahydrofuran, acetone, acetonitrile, n-hexane, cyclohexane, N,N'-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; The base is one or a mixture of two or more of cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium phosphate, lithium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, potassium methoxide, lithium methoxide, triethylamine, N,N,N',N'-tetramethylethylenediamine and tetramethylguanidine; The organic solvent used for the dissolution is one or a mixture of two or more of ethylene glycol dimethyl ether, ethylene dichloride, tetrahydrofuran, cyclohexane, 1,4-dioxane, toluene, acetonitrile, dimethyl sulfoxide, methyl tert-butyl ether, ether, acetone, methyl ethyl ketone, N,N'-dimethylformamide and N,N'-dimethylacetamide; The amount of the base added is 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I); The amount of the boronating agent added is 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I); The amount of the halogenating agent added is 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I); The reaction temperature of the reaction in step (1) is 0 to 150° C., and the reaction time is 1 to 48 hours; The reaction temperature of the halogenation reaction is 0 to 150° C., and the reaction time is 1 to 48 hours; The added amount of the ligand is 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I).

3. The synthesis method according to claim 2, characterized in that The organic solvent in step (1) is toluene; The base is sodium tert-butoxide; The organic solvent used for the dissolution is acetone; The amount of the base added is 10 to 100% molar equivalent of the aldehyde or ketone compound (I); The amount of the boronating agent added is 110% molar equivalent of the aldehyde or ketone compound (I); The amount of the halogenating agent added is 200 to 500% molar equivalent of the aldehyde or ketone compound (I); The reaction temperature of the reaction in step (1) is 25 to 80° C., and the reaction time is 5 to 12 hours; The reaction temperature of the halogenation reaction is room temperature and the reaction time is 12h; The added amount of the ligand is 5-10% molar equivalent of the aldehyde or ketone compound (I).

4. The synthesis method according to claim 1, characterized in that An additive is also added in step (1); The additive is one or a mixture of two or more of methanol, ethanol, tert-butyl alcohol, isopropanol, hexafluoroisopropanol, benzyl alcohol, ethylene glycol and glycerol; The additive is added in an amount of 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I).

5. The synthesis method according to claim 4, characterized in that The additive is methanol; The additive is added in an amount of 150 to 500% molar equivalent of the aldehyde or ketone compound (I).

6. The synthesis method according to claim 1, characterized in that The specific structural formula of the α-halogenated borate compound is: or 7. A method for synthesizing an α-halogenated borate compound, characterized in that: The steps are as follows: (1) Under an inert gas atmosphere, a catalyst, a ligand, a base and a boronating agent are dissolved in an organic solvent, and then an aldehyde or ketone compound (I) is added for reaction. The structural formula of the aldehyde or ketone compound (I) is as follows: Wherein R1 and R2 are hydrogen atoms, aryl groups, alkyl groups or substituted alkyl groups, and R1 and R2 are directly connected to form a closed ring structure or are not directly connected to form an open ring structure; The catalyst is cuprous chloride, the ligand is L1 or L2, the boronating agent is biboric acid pinacol ester, and the structural formulas of L1 and L2 are respectively: (2) cooling and concentrating, dissolving, adding a halogenating agent to carry out a halogenation reaction, and then concentrating, purifying and separating to obtain an α-halogenated borate compound, wherein the halogenating agent is trimethylsilyl chloride; The α-halogenated borate compound is a compound having a structure as shown in formula (III) or an enantiomer structure and a racemic structure of the compound having a structure as shown in formula (III); Wherein R1 and R2 are hydrogen atoms, aryl groups, alkyl groups or substituted alkyl groups, R1 and R2 are directly connected to form a closed ring structure or are not directly connected to form an open ring structure, and the structural formula of BPin is as follows:

8. The synthesis method according to claim 7, characterized in that The inert gas is nitrogen, helium, neon or argon; The organic solvent in step (1) is one or a mixture of two or more of benzene, toluene, xylene, trimethylbenzene, trifluorotoluene, chlorobenzene, ethylene glycol dimethyl ether, anisole, methyl tert-butyl ether, dichloromethane, dichloroethane, chloroform, ethyl acetate, 1,4-dioxane, ether, tetrahydrofuran, acetone, acetonitrile, n-hexane, cyclohexane, N,N'-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; The base is one or a mixture of two or more of cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium phosphate, lithium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, potassium methoxide, lithium methoxide, triethylamine, N,N,N',N'-tetramethylethylenediamine and tetramethylguanidine; The organic solvent used for the dissolution is one or a mixture of two or more of ethylene glycol dimethyl ether, ethylene dichloride, tetrahydrofuran, cyclohexane, 1,4-dioxane, toluene, acetonitrile, dimethyl sulfoxide, methyl tert-butyl ether, ether, acetone, methyl ethyl ketone, N,N'-dimethylformamide and N,N'-dimethylacetamide; The amount of the base added is 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I); The amount of the boronating agent added is 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I); The amount of the halogenating agent added is 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I); The reaction temperature of the reaction in step (1) is 0 to 150° C., and the reaction time is 1 to 48 hours; The reaction temperature of the halogenation reaction is 0 to 150° C., and the reaction time is 1 to 48 hours; The amount of the ligand added is 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I); An additive is also added in step (1); The additive is one or a mixture of two or more of methanol, ethanol, tert-butyl alcohol, isopropanol, hexafluoroisopropanol, benzyl alcohol, ethylene glycol and glycerol; The additive is added in an amount of 0.01 to 2000% molar equivalent of the aldehyde or ketone compound (I).

9. The synthesis method according to claim 8, characterized in that The organic solvent in step (1) is toluene; The base is sodium tert-butoxide; The organic solvent used for the dissolution is acetone; The amount of the base added is 10 to 100% molar equivalent of the aldehyde or ketone compound (I); The amount of the boronating agent added is 110% molar equivalent of the aldehyde or ketone compound (I); The amount of the halogenating agent added is 200 to 500% molar equivalent of the aldehyde or ketone compound (I); The reaction temperature of the reaction in step (1) is 25 to 80° C., and the reaction time is 5 to 12 hours; The reaction temperature of the halogenation reaction is room temperature and the reaction time is 12h; The amount of the ligand added is 5 to 10% molar equivalent of the aldehyde or ketone compound (I); The additive is methanol; The additive is added in an amount of 150 to 500% molar equivalent of the aldehyde or ketone compound (I).

10. The synthesis method according to claim 7, characterized in that: The specific structural formula of the α-halogenated borate compound is: or

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