Synthesis method of alkyl gem-di-pinacol borate compound

Abstract

The invention relates to a synthesis method of an alkyl gem-di-pinacol borate compound, which comprises the following steps: by taking alkyl sulfonium salt and bis (pinacolato) diboron as reaction raw materials, adding an alkali reagent and toluene as solvents, and reacting for 8 hours in a nitrogen atmosphere at room temperature. And after the reaction is finished, obtaining a series of alkyl gem-diboron compounds with high yield. The reaction conditions are mild, the operation is simple and convenient, a reliable experimental method is provided for synthesizing the alkyl gem-diboron compound, and the method has a very good industrial application prospect.

Description

Technical Field

[0001] The invention belongs to the field of organic boron chemical synthesis, and specifically relates to a method for synthesizing an alkyl geminal dipinacol borate compound. Background Art

[0002] Organic boron compounds are widely used in the fields of medicine and pesticides, which attracted chemists to conduct synthetic research on organic compounds containing boric acid pinacol ester functional groups.

[0003] Organoboron compounds are not only widely used in bioactive molecules, natural products and drug molecules, but also as important intermediates in organic reactions, they are widely used in organic chemical synthesis. Among them, alkyl gem-dipinacol borate compounds play a very important role in the synthesis of polysubstituted alkyl compounds. In the past decade, the preparation of alkyl gem-dipinacol borate compounds has aroused the research interest of organic chemists.

[0004] There are documents (Org. Biomol. Chem. 2018, 16, 1050-1064) reporting that compounds such as alkyl geminal dibromines, sulfonylhydrazones, aldehydes and ketones, alkenes, alkynes, etc. can react with boron reagents under transition metal catalysis or strong base conditions to generate corresponding alkyl geminal dipinacol borate compounds. However, the organic synthesis method of synthesizing alkyl geminal dipinacol borate compounds using alkyl sulfonium salts as reaction substrates has not been reported, wherein alkyl sulfonium salts can be rapidly synthesized using alkyl alcohols as raw materials (Angew. Chem. Int. Ed. 2021, 60, 21756-21760). We have developed a method for synthesizing alkyl geminal dipinacol borate esters with mild reaction conditions and simple operation without the participation of transition metals, using convenient and readily available alkyl sulfonium salts as raw materials. Summary of the invention

[0005] The invention aims to provide a method for synthesizing an alkyl geminal dipinacol borate compound. The method has convenient and readily available raw materials, high reaction efficiency, mild reaction conditions, simple operation and good industrial application prospects.

[0006] A method for synthesizing an alkyl geminal dipinacol borate compound, characterized in that the method comprises the following steps:

[0007] Dispersing an alkyl sulfonium salt, bipinacol borate and an alkali reagent in an organic solvent, mixing and reacting, and obtaining an alkyl geminal dipinacol borate compound after the reaction is completed;

[0008] The structural formula of the alkyl sulfonium salt is: The structural formula of the described biboric acid pinacol ester is: The structural formula of the alkyl geminal dipinacol borate compound is

[0009] The alkyl sulfonium salt is selected from any one or more of the following:

[0010]

[0011] In one embodiment of the present invention, the reaction temperature is room temperature (20-30° C.) and the reaction time is 12 h.

[0012] In one embodiment of the present invention, the alkaline reagent is selected from any one or more of the following: lithium tert-butoxide, potassium tert-butoxide, sodium methoxide. Specifically, lithium tert-butoxide can be selected.

[0013] In one embodiment of the present invention, the organic solvent is selected from any one or more of the following: toluene, tetrahydrofuran, and dichloromethane. Specifically, toluene can be selected.

[0014] In one embodiment of the present invention, the molar ratio of the alkyl sulfonium salt to the bipyralidone borate is 1:1.5.

[0015] In one embodiment of the present invention, the alkaline reagent includes any one or more of the following: lithium tert-butoxide, potassium tert-butoxide, and lithium tert-butoxide is particularly preferred.

[0016] In one embodiment of the present invention, the molar ratio of the alkyl sulfonium salt to the alkaline reagent is 1:2.

[0017] In one embodiment of the present invention, the amount of the organic solvent used is 2 mL / 0.2 mmol of the alkyl sulfonium salt reagent, i.e. 10 mL / mmol of the alkyl sulfonium salt.

[0018] In one embodiment of the present invention, the reaction is carried out under a nitrogen atmosphere.

[0019] In one embodiment of the present invention, the synthetic route of the reaction is as follows:

[0020]

[0021] In one embodiment of the present invention, the alkyl geminal dipinacol borate compound specifically comprises the following structure:

[0022] In one embodiment of the present invention, the substitution in the definition of R includes: substituted or unsubstituted alkyl, substituted or unsubstituted aromatic ring, substituted or unsubstituted aromatic heterocycle; substitution includes one to three substitutions, and the substituents are selected from: C1-12 alkyl, halogen, halogen-substituted C1-12 alkyl, and aryl.

[0023] In one embodiment of the present invention, the alkyl pinacol borate compound specifically comprises the following structure:

[0024]

[0025] In one embodiment of the present invention, the molar ratio of the alkyl sulfonium salt, the pinacol diborate, and the lithium tert-butoxide can be 1:1.5:2.

[0026] In one embodiment of the present invention, the method comprises the following specific steps:

[0027] In a reaction tube with a stirrer, under N2 atmosphere, alkyl sulfonium salt, bipyralidin, lithium tert-butoxide and solvent were added in sequence, and stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by rotary evaporator to obtain a crude product. The crude product was separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally the target compound alkyl gem-pyralidin borate was obtained.

[0028] Beneficial effects:

[0029] The invention uses alkyl sulfonium salt and biboric acid pinacol ester as raw materials, adds lithium tert-butylate, reacts in toluene at room temperature for 12 hours, and obtains alkyl geminal dipinacol borate compound after the reaction is completed. The synthetic method of the invention has simple and easy-to-obtain reaction raw materials, mild reaction conditions, convenient operation, and good industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The schematic diagram of the synthesis method of the present invention is shown in FIG. DETAILED DESCRIPTION

[0031] In order to make the contents of the present invention easier to understand, the technical solution of the present invention is further described below in conjunction with specific implementation methods, but the present invention is not limited to the scope of the embodiments.

[0032] Example 1

[0033] In a reaction tube with a stirrer, under N2 atmosphere, pinacol diboron (0.3mmol, 1.5equiv), 3-phenylpropylsulfonate (0.2mmol, 1equiv), lithium tert-butylate (0.4mmol, 2equiv), toluene solvent (2.0mL) were added in sequence, and stirred at room temperature for 12h. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by a rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to finally obtain the compound of formula 1 (isolation yield 80%).

[0034]

[0035] 1 H NMR (600MHz, CDCl3) δ7.17-7.14 (m, 2H), 7.10-7.04 (m, 3H), 2.51 (t, J = 8.0Hz , 2H), 1.83-1.73 (m, 2H), 1.16 (s, 12H), 1.15 (s, 12H), 0.74 (t, J = 8.0Hz, 1H); 13 C NMR (151MHz, CDCl3) δ142.9, 128.6, 128.2, 125.6, 83.0, 38.8, 28.1, 24.9, 24.6, 10.6; 11 B NMR (193MHz, CDCl3) δ34.2.

[0036] Example 2

[0037] In a reaction tube with a stirrer, under N2 atmosphere, pinacol diboric acid ester (0.3mmol, 1.5equiv), 2-p-fluorophenethyl sulfonate (0.2mmol, 1equiv), lithium tert-butoxide (0.4mmol, 2equiv), toluene solvent (2.0mL) were added in sequence, and stirred at room temperature for 12h. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by a rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to finally obtain the compound of formula 2 (isolation yield 48%).

[0038]

[0039] 1 H NMR (400MHz, CDCl3) δ7.22-7.12 (m, 2H), 6.90 (t, J = 8.8Hz, 2H), 2.84 (d, J = 8.4Hz, 2H), 1.18 (s, 12H), 1.17 (s, 12H), 1.12 (t, J = 8.4Hz, 1H); 13 C NMR (101MHz, CDCl3) δ161.1 (d, J=242.2Hz), 140.1 (d, J=3.0Hz), 129.6 (d, J=7.7Hz), 114.5 (d, J=20.9Hz), 83.1, 30.5, 24.8, 24.5; 11 B NMR (128MHz, CDCl3) δ34.00; 19 F NMR (376MHz, CDCl3) δ -118.65, -118.66, -118.67, -118.68, -118.70, -118.71, -118.72.

[0040] Example 3

[0041] In a reaction tube with a stirrer, under N2 atmosphere, add pinacol diboric acid ester (0.3mmol, 1.5equiv), 3,3-dimethylbutyl sulfide (0.2mmol, 1equiv), lithium tert-butoxide (0.4mmol, 2equiv), toluene solvent (2.0mL) in sequence, and stir at room temperature for 12h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining the compound of formula 3 (isolation yield 47%).

[0042]

[0043] 1 H NMR (600MHz, CDCl3) δ1.45 (d, J=6.6Hz, 2H), 1.15 (s, 12H), 1.14 (s, 12H), 0.76 (s, 9H), 0.66 (t, J=6.6Hz, 1H); 13 C NMR (101MHz, CDCl3) 682.9, 39.2, 31.6, 29.2, 24.8, 24.6; 11 B NMR (193MHz, CDCl3) δ33.47.

[0044] Example 4

[0045] In a reaction tube with a stirrer, under N2 atmosphere, pinacol diboric acid ester (0.3mmol, 1.5equiv), heptyl sulfide (0.2mmol, 1equiv), lithium tert-butoxide (0.4mmol, 2equiv), toluene solvent (2.0mL) were added in sequence, and stirred at room temperature for 12h. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by a rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to finally obtain a compound of formula 4 (isolation yield 86%).

[0046]

[0047] 1 H NMR (400MHz, CDCl3) δ1.53-1.41 (m, 2H), 1.38-0.92 (m, 32H), 0.79 (t, J = 6.6Hz, 3H), 0.64 (t, J = 8.0Hz, 1H); 13C NMR (101MHz, CDCl3) δ82.8, 32.5, 31.8, 29.3, 25.7, 24.9, 24.5, 22.6, 14.1; 11 B NMR (128 MHz, CDCl3) δ 32.7.

[0048] Example 5

[0049] In a reaction tube with a stirrer, under N2 atmosphere, add pinacol diboric acid ester (0.3mmol, 1.5equiv), 3,5,5-trimethylhexyl sulfide (0.2mmol, 1equiv), lithium tert-butoxide (0.4mmol, 2equiv), toluene solvent (2.0mL) in sequence, and stir at room temperature for 12h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 5 (isolation yield 86%).

[0050]

[0051] 1 H NMR (400MHz, CDCl3) δ1.58-1.49 (m, 1H), 1.43-1.04 (m, 27H), 0.96-0.89 (m, 1H), 0.86-0.75 (m, 13H); 13 C NMR (101MHz, CDCl3) δ82.9, 51.3, 35.2, 31.5, 31.2, 30.1, 24.9, 24.6, 24.6, 22.3, 8.5; 11 B NMR (128 MHz, CDCl3) δ 33.8.

[0052] Example 6

[0053] In a reaction tube with a stirrer, under N2 atmosphere, pinacol diboric acid ester (0.3mmol, 1.5equiv), methyl sulfide (0.2mmol, 1equiv), lithium tert-butoxide (0.4mmol, 2equiv), toluene solvent (2.0mL) were added in sequence, and stirred at room temperature for 12h. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by a rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to finally obtain a compound of formula 6 (isolation yield 71%).

[0054]

[0055] 1 H NMR (600MHz, CDCl3) δ1.22 (s, 24H), 0.34 (s, 2H); 13 C NMR (151MHz, CDCl3) δ83.1, 24.9. 11 B NMR (193MHz, CDCl3) δ33.6.

[0056] Example 7

[0057] In a reaction tube with a stirrer, under N2 atmosphere, add pinacol diboric acid ester (0.3mmol, 1.5equiv), 2-thiophene ethyl sulfide (0.2mmol, 1equiv), lithium tert-butoxide (0.4mmol, 2equiv), toluene solvent (2.0mL) in sequence, and stir at room temperature for 12h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to finally obtain the compound of formula 7 (isolation yield 47%).

[0058]

[0059] 1 H NMR (400MHz, CDCl3) δ7.03 (d, J=4.2Hz, 1H), 6.88-6.75 (m, 2H), 3.08 (d, J=8.2Hz, 2H), 1.20 (s, 12H), 1.19 (s, 13H); 13 C NMR (101MHz, CDCl3) δ148.0, 126.3, 123.7, 122.4, 83.2, 25.8, 24.8, 24.5; 11 B NMR (128MHz, CDCl3) δ33.6.

[0060] Example 8

[0061] In a reaction tube with a stirrer, under N2 atmosphere, pinacol diboric acid ester (0.3mmol, 1.5equiv), amyl sulfide (0.2mmol, 1equiv), lithium tert-butoxide (0.4mmol, 2equiv), toluene solvent (2.0mL) were added in sequence, and stirred at room temperature for 12h. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by a rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to finally obtain a compound of formula 8 (isolation yield 68%).

[0062]

[0063] 1 H NMR (400MHz, CDCl3) δ1.53-1.45 (m, 2H), 1.28-1.10 (m, 28H), 0.81 (t, J = 6.8Hz, 3H), 0.66 (t, J = 8.0Hz, 1H); 13 C NMR (101MHz, CDCl3) δ82.9, 34.9, 25.4, 24.9, 24.6, 22.7, 14.2, 10.7; 11 B NMR (128 MHz, CDCl3) δ 32.7.

[0064] Example 9

[0065] In a reaction tube with a stirrer, under N2 atmosphere, pinacol diboric acid ester (0.3mmol, 1.5equiv), 2-cyclopentylethyl sulfide (0.2mmol, 1equiv), lithium tert-butoxide (0.4mmol, 2equiv), toluene solvent (2.0mL) were added in sequence, and stirred at room temperature for 12h. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by a rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to finally obtain a compound of formula 9 (isolation yield 78%).

[0066]

[0067] 1 H NMR (400MHz, CDCl3) δ1.72-1.65 (m, 3H), 1.58-1.50 (m, 4H), 1.47-1.40 (m, 2H), 1.20 (s, 24H), 1.07-0.99 (m, 2H), 0.7-0.94 (m, 1H); 13 C NMR (100MHz, CDCl3) δ82.9, 42.7, 32.5, 31.7, 25.2, 24.8, 24.6; 11 B NMR (128 MHz, CDCl3) δ 33.9.

[0068] Example 10

[0069] In a reaction tube with a stirrer, under N2 atmosphere, pinacol diboric acid ester (0.3mmol, 1.5equiv), ethyl sulfide (0.2mmol, 1equiv), lithium tert-butoxide (0.4mmol, 2equiv), toluene solvent (2.0mL) were added in sequence, and stirred at room temperature for 12h. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by a rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to finally obtain a compound of formula 10 (isolation yield 47%).

[0070]

[0071] 1 H NMR (600MHz, CDCl3) δ1.19 (s, 12H), 1.19 (s, 12H), 1.00 (d, J=7.2Hz, 3H), 0.69 (q, J=7.2Hz, 1H); 13 C NMR (151MHz, CDCl3) δ82.9, 24.9, 24.6, 9.1, 2.2; 11 B NMR (193MHz, CDCl3) δ34.0.

[0072] Embodiment 11

[0073] In a reaction tube with a stirrer, under N2 atmosphere, pinacol diboron (0.3mmol, 1.5equiv), 2-adamantane ethyl sulfide (0.2mmol, 1equiv), lithium tert-butoxide (0.4mmol, 2equiv), toluene solvent (2.0mL) were added in sequence, and stirred at room temperature for 12h. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by a rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to finally obtain a compound of formula 11 (isolation yield 53%).

[0074]

[0075] 1 H NMR (400MHz, CDCl3) δ1.91 (brs, 3H), 1.66 (d, J = 12.5Hz, 3H), 1.61-1.56 (m, 3H), 1.44-1.36 (m, 8H), 1.22 (d, J = 0.8Hz, 24H), 0.75 (t, J = 6.7Hz, 1H); 13C NMR (100MHz, CDCl3) δ82.9, 42.149, 39.7, 37.3, 33.2, 28.8, 24.8, 24.6; 11 B NMR (128 MHz, CDCl3) δ 34.3.

[0076] Example 12

[0077] In a reaction tube with a stirrer, under N2 atmosphere, pinacol diboron (0.3mmol, 1.5equiv), 4,4,5,5,5-pentafluoropentylsulfonate (0.2mmol; 1equiv), lithium tert-butoxide (0.4mmol, 2equiv), toluene solvent (2.0mL) were added in sequence, and stirred at room temperature for 12h. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by a rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to finally obtain the compound of formula 12 (isolation yield 56%).

[0078]

[0079] 1 H NMR (400MHz, CDCl3) δ2.15-1.95 (m, 2H), 1.90-1.75 (m, 2H), 1.24 (s, 12H), 1.22 (s, 12H), 0.75 (t, J=7.8Hz, 1H); 13 C NMR (101MHz, CDCl3) δ83.3, 32.5 (t, J=21.7Hz), 24.9, 24.4, 16.4; 19 F NMR (376MHz, CDCl3) δ-85.5, -118.2; 11 B NMR (128 MHz, CDCl3) δ 33.3.

[0080] Example 13 Synthesis of target product using different alkaline reagents

[0081] In a reaction tube with a stirrer, under N2 atmosphere, add pinacol diboronate (0.3 mmol, 1.5 equiv), alkyl sulfonium salt reagent (0.2 mmol, 1 equiv), base (0.4 mmol, 2 equiv), and 2 mL of organic solvent in sequence, and stir at room temperature for 12 h. The reaction results are shown in Table 1.

[0082] Table 1 Synthesis results of different alkaline reagents

[0083] Alkaline reagent The NMR yield of the compound of formula 1 Lithium tert-butoxide 89％ Potassium tert-butoxide 83％ Sodium Methanol 46％

[0084] Example 14 Synthesis of target product using different organic solvents

[0085] In a reaction tube with a stirrer, under N2 atmosphere, pinacol diboronate (0.3 mmol, 1.5 equiv), alkyl sulfonium salt reagent (0.2 mmol, 1 equiv), base (0.4 mmol, 2 equiv), and 2 mL of organic solvent were added in sequence, and stirred at room temperature for 12 h. The reaction results are shown in Table 2.

[0086] Table 2 Synthesis results of different organic solvents

[0087] Organic solvents The NMR yield of the compound of formula 1 Toluene 89％ Dichloromethane 83％ Tetrahydrofuran 52％

[0088] Although the present invention has been described by the specific embodiments above, it should not be construed as being limited thereto; rather, the present invention encompasses the general aspects disclosed above. Various modifications and various embodiments are possible without departing from the spirit and scope of the present invention.

Claims

1. A method for synthesizing an alkyl geminal dipinacol borate compound, characterized in that: The method comprises the following steps: Dispersing an alkyl sulfonium salt, bipinacol borate and an alkali reagent in an organic solvent, mixing and reacting, and obtaining an alkyl geminal dipinacol borate compound after the reaction is completed; The structural formula of the alkyl sulfonium salt is: The structural formula of the described biboric acid pinacol ester is: The structural formula of the alkyl geminal dipinacol borate compound is The alkyl sulfonium salt is selected from any one or more of the following: The alkaline reagent is selected from any one or more of the following: lithium tert-butoxide, potassium tert-butoxide, sodium methoxide; The organic solvent is selected from any one or more of the following: toluene, tetrahydrofuran, and dichloromethane.

2. The method according to claim 1, characterized in that The synthetic route of the reaction is as follows:

3. The method according to claim 1, characterized in that The molar ratio of the alkyl sulfonium salt to the biboric acid pinacol ester is 1:1.

5.

4. The method according to claim 1, characterized in that: The molar ratio of the alkyl sulfonium salt to the base reagent is 1:2.

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