A method for synthesizing a bis(diol-boryl)methane compound

Abstract

This invention discloses a method for synthesizing bis(diolboryl)methane, which achieves the synthesis of bis(diolboryl)methane compounds through the reaction of diol borate ester with in-situ generated sulfur ylides. The method uses tetrahydrofuran or N,N-dimethylformamide as the reaction solvent and sodium hydride as the base, reacting at room temperature. The raw materials used are simple and readily available, and the operation is straightforward. This method is also highly reliable for gram-scale and above preparations.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing bis(diolboryl)methane compounds. Background Technology

[0002] Bis(diolboryl)methane is an important organic synthesis intermediate. It can undergo deboron coupling reactions to generate a variety of relatively complex organoboroesters, or undergo alkylation reactions under strongly basic conditions to obtain higher geminoboroesters. The latter can be converted into a variety of valuable organic compounds through catalytic or non-catalytic processes. Among the compounds of the bis(diolboryl)methane type, bis[(pinacol)boryl]methane is the most representative and the most studied.

[0003] There are currently five known methods for synthesizing bis(pinacol)boron methane. The first method is a copper- or manganese-catalyzed coupling reaction of dibromomethane with pinacol diboron ester. The second method is an insertion reaction of diazonium methane with pinacol diboron ester under tetra(triphenylphosphine)platinum catalysis. The third method is a methylene insertion reaction of dihalomethane with pinacol diboron ester in the presence of a Grignard reagent. The fourth method is a copper-catalyzed reaction of formaldehyde with pinacol diboron ester. The fifth method is a rhodium-catalyzed reaction of carbon monoxide with pinacol diboron ester in the presence of silane. However, these methods require expensive transition metal catalysts or metal reagents, or some reactions require more than two equivalents of pinacol diboron ester, resulting in low atom utilization. Furthermore, pinacol diboron ester is a relatively expensive raw material. Therefore, these methods do not conform to the principles of a green economy, have high production costs, and are not conducive to the large-scale production of bis(pinacol)boron methane. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a method for synthesizing bis(diolboryl)methane compounds, comprising the following steps: in an inert gas atmosphere and in the presence of a base, the compound shown in formula (A) reacts with the compound shown in formula (B) to obtain the compound shown in formula (C).

[0005]

[0006] in, This represents a 5- or 6-membered heterocycle containing B and O, wherein the 5- or 6-membered heterocycle is unsubstituted or optionally substituted by one, two or more C atoms. 1-6 Alkyl substitution;

[0007] X is a halogen, that is, the compound shown in formula (B) is trimethyl sulfoxide or trimethyl sulfoxide.

[0008] According to an embodiment of the present invention, the C 1-6The alkyl group is selected from straight-chain or branched saturated monovalent hydrocarbon groups with 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl or 1,2-dimethylpropyl.

[0009] In one embodiment of the invention, the compound shown in formula (A) contains... The following ring systems are substituted with one, two, three or four methyl groups: 5- or 6-membered heterocycles containing B and O, for example, the compound shown in formula (A) is selected from pinacol diborate, neopentyl diborate, bis(2-methyl-2,4-pentanediol)borate or bis(2,4-dimethyl-2,4-pentanediol)borate.

[0010] In one embodiment of the present invention, the compound represented by formula (B) is trimethyl sulfoxide, trimethyl sulfoxide, trimethyl sulfonium bromide, or trimethyl sulfonium iodide.

[0011] In one embodiment of the invention, the alkali is sodium hydride.

[0012] In one embodiment of the present invention, the reaction solvent is tetrahydrofuran or N,N-dimethylformamide.

[0013] In one embodiment of the invention, the reaction temperature is -5 to 40°C, for example, 0 to 30°C.

[0014] In one embodiment of the invention, the molar concentration of the compound represented by formula (A) in the solvent is 0.1-2 mol / L, for example, 0.25 mol / L, 0.5 mol / L, 0.67 mol / L or 1 mol / L, calculated as a molar ratio.

[0015] In one embodiment of the invention, the molar concentration of the compound represented by formula (B) in the solvent is 0.1-2 mol / L, for example, 0.35 mol / L, 0.75 mol / L, 1 mol / L or 1.5 mol / L, calculated as a molar ratio.

[0016] In one embodiment of the invention, the molar ratio of the compound shown in formula (A) to the base is 1:(1.1-2), for example, 1:1.4 or 1:1.7.

[0017] In one embodiment of the invention, the reaction time is 6 hours to 8 days, for example, 12 hours to 6 days.

[0018] In one embodiment of the invention, the inert gas atmosphere is provided by nitrogen.

[0019] In one embodiment of the present invention, the compound shown in (C) is prepared according to the following steps when tetrahydrofuran is used as a solvent:

[0020] Add the compound shown in formula (A), the compound shown in formula (B), and a base to a reaction flask, then protect the reaction under a nitrogen atmosphere, add tetrahydrofuran, and stir the reaction at -5 to 40°C for 12 hours to 6 days.

[0021] In one embodiment of the present invention, the compound shown in (C) is prepared according to the following steps when N,N-dimethylformamide is used as a solvent:

[0022] Add a base and the compound shown in formula (B) to a reaction flask, then add N,N-dimethylformamide under a nitrogen atmosphere. First, stir the reaction at 0°C for 1-30 min, then stir the reaction at -5-40°C for 1-60 min. Then, add the compound shown in formula (A) under a nitrogen atmosphere and continue stirring the reaction for 6 hours to 6 days.

[0023] Beneficial effects

[0024] The inventors have discovered that, under alkaline conditions, diboronic acid diol ester reacts with in-situ generated sulfur ylide via a methylene insertion reaction to yield bis(diolboryl)methane compounds.

[0025] Specifically, the method of the present invention has the following advantages and innovations:

[0026] (1) The raw materials include the compounds shown in formula (A) and formula (B), both of which are simple and readily available;

[0027] (2) The two boron groups in the slightly more expensive raw material (A) diboronic acid ester are all converted into the product, resulting in high atom utilization and conforming to the principle of green economy.

[0028] (3) The solvents tetrahydrofuran or N,N-dimethylformamide are inexpensive, have low boiling points, and are easy to recover;

[0029] (4) The reaction is carried out at a lower temperature, which is convenient for practical operation;

[0030] (5) It can be prepared in gram scale, and the reaction is suitable for large-scale preparation.

[0031] In summary, this invention is the first to use diboronate diol ester and trimethyl sulfoxide or trimethyl sulfoxide to prepare bis(diolboron)methane compounds. The raw materials and reaction solvents used are simple and readily available. Diboronate diol ester has high utilization rate. The reaction process is simple and the conditions are mild, making it suitable for large-scale preparation.

[0032] Terminology Definitions and Explanations

[0033] In this article, when describing one, two, or more species, "more species" should refer to the case of more than 2, such as the case of integers greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9, or 10 species.

[0034] In this document, the term "optional" means either the presence or absence of the described feature, implying that the event subsequently described may but is not necessarily to occur, and thus includes both cases where the event occurs or does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but is not necessarily present, and thus includes cases where the heterocyclic group is alkyl-substituted and cases where the heterocyclic group is not alkyl-substituted. Attached Figure Description

[0035] Figure 1 The image shows the 1H NMR spectrum (500MHz, CDCl3) of compound 3a.

[0036] Figure 2 The image shows the 1H NMR spectrum (400MHz, CDCl3) of compound 3b.

[0037] Figure 3 The image shows the 1H NMR spectrum of compound 3c (500MHz, CDCl3).

[0038] Figure 4 The image shows the carbon NMR spectrum of compound 3c (125 MHz, CDCl3).

[0039] Figure 5 The image shows the 1H NMR spectrum of compound 3d (400MHz, CDCl3).

[0040] Figure 6 The image shows the carbon NMR spectrum of compound 3d (125 MHz, CDCl3). Detailed Implementation

[0041] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0042] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0043] Example 1

[0044]

[0045] In a Schlenk flask, a magnetic stir bar, compound 1a (1270 mg, 5 mmol), trimethyl sulfoxide 2a (1540 mg, 7 mmol), and sodium hydride (340 mg, 8.5 mmol) were added sequentially. The mixture was then placed under a nitrogen atmosphere, followed by the addition of tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 3 days. The reaction solution was quenched with ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography to give compound 3a (white solid, 696 mg, yield 52%).

[0046] 1 H NMR (500MHz, CDCl3): δ1.24(s,24H),0.35(s,2H). 13 C NMR (125MHz, CDCl3): δ83.0,24.7.

[0047] Example 2

[0048]

[0049] In a Schlenk flask, a magnetic stir bar, sodium hydride (560 mg, 14 mmol), and trimethyl sulfoxide 2a (3300 mg, 15 mmol) were added sequentially. Under a nitrogen atmosphere, N,N-dimethylformamide (10 mL) was added. The mixture was stirred at 0 °C for 15 min, then at room temperature for approximately 30 min. Compound 1a (2540 mg, 10 mmol) was then added under a nitrogen atmosphere, and the reaction was continued for 12 hours. The reaction mixture was slowly quenched in ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography to give compound 3a (white solid, 1520 mg, 55% yield).

[0050] 1 H NMR (500MHz, CDCl3): δ1.24(s,24H),0.35(s,2H). 13 C NMR (125MHz, CDCl3): δ83.0,24.7.

[0051] Example 3

[0052]

[0053] In a Schlenk flask, a magnetic stir bar, sodium hydride (560 mg, 14 mmol), and trimethylsulfonium iodide 2b (3060 mg, 15 mmol) were added sequentially. Under a nitrogen atmosphere, N,N-dimethylformamide (20 mL) was added. The mixture was stirred at 0 °C for 15 min, then at room temperature for approximately 30 min. Compound 1a (2540 mg, 10 mmol) was then added under a nitrogen atmosphere, and the reaction was continued for 6 days. The reaction mixture was slowly quenched in ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent removed by vacuum distillation. Trimethylamine dihydrate (222 mg, 2 mmol) was added to the residue to remove unreacted compound 1a, followed by 10 mL of acetonitrile. The mixture was stirred at room temperature for 2 hours, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography to give compound 3a (white solid, 1087 mg, yield 41%).

[0054] 1 H NMR (500MHz, CDCl3): δ1.24(s,24H),0.35(s,2H). 13 C NMR (125MHz, CDCl3): δ83.0,24.7.

[0055] Example 4

[0056]

[0057] In a Schlenk flask, a magnetic stir bar, compound 1a (1270 mg, 5 mmol), trimethyl thionyl chloride 2c (903 mg, 7 mmol), and sodium hydride (340 mg, 8.5 mmol) were added sequentially. The mixture was then placed under a nitrogen atmosphere, followed by the addition of tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 3 days. The reaction solution was slowly poured into ice water to quench the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. Trimethylamine dihydrate (333 mg, 3 mmol) and 15 mL of acetonitrile were added to the residue, and the mixture was stirred at room temperature for 2.5 hours. The solvent was removed by vacuum distillation, and the residue was purified by column chromatography to give compound 3a (white solid, 425 mg, yield 32%).

[0058] 1 H NMR (500MHz, CDCl3): δ1.24(s,24H),0.35(s,2H). 13 C NMR (125MHz, CDCl3): δ83.0,24.7.

[0059] Example 5

[0060]

[0061] In a Schlenk flask, a magnetic stir bar, sodium hydride (560 mg, 14 mmol), and trimethyl thionyl chloride 2c (1935 mg, 15 mmol) were added sequentially. Under a nitrogen atmosphere, N,N-dimethylformamide (10 mL) was added. The mixture was stirred at 0 °C for 15 min, then at room temperature for approximately 30 min. Compound 1a (2540 mg, 10 mmol) was then added under a nitrogen atmosphere, and the reaction was continued for 12 hours. The reaction solution was slowly quenched in ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. Trimethylamine dihydrate (222 mg, 2 mmol) and 10 mL of acetonitrile were added to the residue, and the mixture was stirred at room temperature for 2 hours. The solvent was removed by vacuum distillation, and the residue was purified by column chromatography to give compound 3a (white solid, 828 mg, yield 31%).

[0062] 1 H NMR (500MHz, CDCl3): δ1.24(s,24H),0.35(s,2H). 13 C NMR (125MHz, CDCl3): δ83.0,24.7.

[0063] Example 6

[0064]

[0065] In a Schlenk flask, a magnetic stir bar, sodium hydride (560 mg, 14 mmol), and trimethylsulfonium bromide 2d (2355 mg, 15 mmol) were added sequentially. Under a nitrogen atmosphere, N,N-dimethylformamide (20 mL) was added. The mixture was stirred at 0 °C for 15 min, then at room temperature for approximately 60 min. Compound 1a (2540 mg, 10 mmol) was then added under a nitrogen atmosphere, and the reaction was continued for 6 days. The reaction mixture was slowly quenched in ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent removed by vacuum distillation. Trimethylamine dihydrate (222 mg, 2 mmol) and 10 mL of acetonitrile were added to the residue, and the mixture was stirred at room temperature for 3 hours. The solvent was removed by vacuum distillation, and the residue was purified by column chromatography to give compound 3a (white solid, 390 mg, yield 15%).

[0066] 1 H NMR (500MHz, CDCl3): δ1.24(s,24H),0.35(s,2H). 13 C NMR (125MHz, CDCl3): δ83.0,24.7.

[0067] Example 7

[0068]

[0069] In a Schlenk flask, a magnetic stir bar, sodium hydride (560 mg, 14 mmol), and trimethyl sulfoxide 2a (3300 mg, 15 mmol) were added sequentially. Under a nitrogen atmosphere, N,N-dimethylformamide (15 mL) was added. The mixture was stirred at 0°C for 15 min, then at room temperature for approximately 30 min. Compound 1b (2260 mg, 10 mmol) was then added under a nitrogen atmosphere, and the reaction was continued for 12 hours. The reaction mixture was slowly quenched in ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography to give compound 3b (white solid, 261 mg, 11%).

[0070] 1 H NMR (400MHz, CDCl3): δ3.59(s,8H),0.95(s,12H),0.24(s,2H).

[0071] Example 8

[0072]

[0073] In a Schlenk flask, a magnetic stir bar, sodium hydride (560 mg, 14 mmol), and trimethyl sulfoxide 2a (3300 mg, 15 mmol) were added sequentially. Under a nitrogen atmosphere, N,N-dimethylformamide (10 mL) was added. The mixture was stirred at 0 °C for 15 min, then at room temperature for approximately 30 min. Compound 1c (2540 mg, 10 mmol) was then added under a nitrogen atmosphere, and the reaction was continued for 12 hours. The reaction solution was slowly quenched in ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography to give compound 3c (colorless liquid, 1296 mg, yield 48%).

[0074] 1 H NMR (500MHz, CDCl3): δ4.17-4.14(m,2H),1.72(dd,J=15.0,5.0Hz,2H),1.47-1.42(m,2H),1.26(s,12H),1.23(d,J=5Hz,6H),0.14(s,2H). 13 C NMR (125MHz, CDCl3): δ70.4, 64.5, 45.9, 31.3, 28.0, 23.3.

[0075] Example 9

[0076]

[0077] In a Schlenk flask, a magnetic stir bar, sodium hydride (560 mg, 14 mmol), and trimethyl sulfoxide 2a (3300 mg, 15 mmol) were added sequentially. Under a nitrogen atmosphere, N,N-dimethylformamide (10 mL) was added. The mixture was stirred at 0 °C for 15 min, then at room temperature for approximately 30 min. Compound 1d (2820 mg, 10 mmol) was then added under a nitrogen atmosphere, and the reaction was continued for 12 hours. The reaction mixture was slowly quenched in ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography to give compound 3d (white solid, 2118 mg, yield 72%).

[0078] 1 H NMR (400MHz, CDCl3): δ1.78(s,4H),1.32(s,24H),0.17(s,2H). 13 CNMR (125MHz, CDCl3): δ70.2, 48.8, 31.8.

[0079] Example 10

[0080]

[0081] In a Schlenk flask, a magnetic stir bar, compound 1d (1410 mg, 5 mmol), trimethyl sulfoxide 2a (1540 mg, 7 mmol), and sodium hydride (340 mg, 8.5 mmol) were added sequentially. The mixture was then placed under a nitrogen atmosphere, followed by the addition of tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 6 days. The reaction solution was quenched with ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography to give compound 3d (white solid, 489 mg, yield 33%).

[0082] 1 H NMR (400MHz, CDCl3): δ1.78(s,4H),1.32(s,24H),0.17(s,2H). 13 CNMR (125MHz, CDCl3): δ70.2, 48.8, 31.8.

[0083] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing bis(diolboryl)methane compounds, characterized in that, The process includes the following steps: In an inert gas atmosphere and in the presence of a base, the compound shown in formula (A) reacts with the compound shown in formula (B) to prepare the compound shown in formula (C). in, This represents a 5- or 6-membered heterocycle containing B and O, wherein the 5- or 6-membered heterocycle is unsubstituted or optionally substituted by one, two or more C atoms. 1-6 Alkyl substitution; X is a halogen, that is, the compound shown in formula (B) is trimethyl sulfoxide or trimethyl sulfoxide; The alkali is sodium hydride; The reaction solvent is tetrahydrofuran or N,N -Dimethylformamide.

2. The method according to claim 1, characterized in that, The C 1-6 The alkyl group is selected from straight-chain or branched saturated monovalent hydrocarbon groups with 1 to 6 carbon atoms.

3. The method according to claim 1, characterized in that, In the compound shown in formula (A) The following ring systems are substituted with one, two, three or four methyl groups: 5- or 6-membered heterocycles containing B and O.

4. The method according to claim 3, characterized in that, The compound shown in formula (A) is selected from pinacol diboronate, neopentyl diboronate, bis(2-methyl-2,4-pentanediol)boronate or bis(2,4-dimethyl-2,4-pentanediol)boronate.

5. The method according to claim 1, characterized in that, The compound shown in formula (B) is trimethyl sulfoxide, trimethyl sulfoxide, trimethyl sulfonium bromide or trimethyl sulfonium iodide.

6. The method according to claim 1, characterized in that, The reaction temperature is -5 to 40°C. o C.

7. The method according to claim 1, characterized in that, Based on molar ratio, the molar concentration of the compound shown in formula (A) in the solvent is 0.1-2 mol / L.

8. The method according to claim 1, characterized in that, Based on molar ratio, the molar concentration of the compound shown in formula (B) in the solvent is 0.1-2 mol / L.

9. The method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (A) to the base is 1:(1.1-2).

10. The method according to claim 1, characterized in that, The reaction time ranges from 6 hours to 8 days.

11. The method according to claim 1, characterized in that, When tetrahydrofuran is used as a solvent, the compound shown in (C) is prepared according to the following steps: Add the compound shown in formula (A), the compound shown in formula (B), and a base to a reaction flask, then protect the reaction flask with a nitrogen atmosphere, add tetrahydrofuran, and react at -5 to -40°C. o React under temperature C for 12 hours to 6 days with stirring; or... When using N,N The compound shown in (C) is prepared using dimethylformamide as a solvent according to the following steps: Add a base and the compound shown in formula (B) to the reaction flask, then protect the reaction flask with a nitrogen atmosphere, and add... N,N -Dimethylformamide, first reacted with stirring at 0 °C for 1-30 min, then at -5-40 °C o Stir the reaction for 1-60 min, then add the compound shown in formula (A) under a nitrogen atmosphere, and continue stirring for 6 hours to 6 days.

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