The invention relates to 1, 1apos; the invention relates to a method for preparing 2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1, 1apos, 2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1, synthesis method of-bis (cyclopropane)
By using a metal halogen exchange-boronization reaction, and by reacting 2,2,6,6-tetramethylpiperidine and n-butyllithium with pinacol diboronate in a low-temperature one-step reaction, 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane) was successfully synthesized. This solved the problems of complex synthetic routes and high costs in existing technologies, and achieved the synthesis of the target compound in high yield.
Patent Information
- Application Number
- CN202511080637.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-04
- Publication Date
- 2025-11-21
AI Technical Summary
No existing methods have been reported for the synthesis of 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane), and existing methods are costly, complex, pose significant safety risks, and have unsatisfactory yields.
The target compound was generated by a metal halide exchange-boronization reaction using 2,2,6,6-tetramethylpiperidine, n-butyllithium, and pinacol diboronate as raw materials in a low-temperature step-by-step reaction.
A low-cost, short-step, and mild reaction condition was achieved for the high-yield synthesis of 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane), providing a simple synthetic route.
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Figure CN120987984A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane). Background Technology
[0002] Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane) compounds are an important class of organic compounds and also important molecular building blocks. For example, 2,2′-(1-cyclopropylethane-1,2-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane) is used as a key intermediate in the synthesis of cyclopropyl diborate in the article "Copper-Catalyzed Synthesis of Stereodefined Cyclopropyl Bis(Boronates) from Alkenes with CO as the C1 Source" published by Xiao-Feng Wu et al.
[0003] The bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane) class of compounds has shown significant economic potential, and 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-di(cyclopropane), as one of these compounds, also possesses high economic viability. Currently, no synthetic route for 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-di(cyclopropane) has been reported. Therefore, further research into its synthetic method will not only benefit the development of this compound but also contribute to the development and utilization of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane) class of compounds. Summary of the Invention
[0004] To address the aforementioned problems in the existing technology, the present invention aims to provide a method for synthesizing 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane). The synthesis process is low-cost, simple and easy to operate, with relatively mild reaction conditions, low safety risks, and ideal yield.
[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0006] This invention provides a method for synthesizing 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane), wherein the reaction type of the synthesis method is a metal halide exchange-boronization reaction.
[0007] Preferably, the synthetic route of the synthetic method is as follows:
[0008]
[0009] Specifically, it includes the following steps:
[0010] (1) Add 2,2,6,6-tetramethylpiperidine to organic solvent I. Under inert gas protection, add n-butyllithium solution dropwise at -80℃ to -50℃. After the addition is complete, naturally raise the temperature to -5℃ to 5℃ and react for 20-40 minutes. Then lower the temperature to -80℃ to -50℃ and add pinacol ester of borate and organic solvent II solution of compound 1, i.e. bromocyclopropane. Stir at -80℃ to -50℃ for 0.5-3 hours, and then stir at room temperature for 8-40 hours.
[0011] (2) After the reaction is completed, the resulting reaction solution is post-treated to obtain target compound 2, namely 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane).
[0012] Preferably, in step (1), the organic solvent I is selected from one or more of tetrahydrofuran, diethyl ether, or methyl tert-butyl ether.
[0013] Preferably, in step (1), the inert gas is nitrogen and / or argon.
[0014] Preferably, in step (1), the n-butyllithium solution is one or more of the following: n-butyllithium dissolved in n-hexane solution, n-butyllithium dissolved in n-ethane solution, and n-butyllithium dissolved in tetrahydrofuran solution.
[0015] Preferably, in step (1), the organic solvent II is selected from one or more of tetrahydrofuran, diethyl ether, or methyl tert-butyl ether.
[0016] Preferably, in step (1), the molar ratio of compound 1 to 2,2,6,6-tetramethylpiperidine is 1:1-3. Preferably, in step (1), the molar ratio of compound 1 to pinacol diboronate is 1:1-3. Preferably, in step (1), the molar ratio of compound 1 to n-butyllithium solution is 1:1-3.
[0017] Preferably, in step (1), the mass-to-volume ratio of compound 1 to organic solvent I is 1:5-40 g / mL.
[0018] Preferably, in step (1), the mass-to-volume ratio of compound 1 to organic solvent II is 1:5-40 g / mL.
[0019] Preferably, in step (2), the post-processing includes: after the reaction is complete, water is added to the reaction solution, and the solution is extracted with organic solvent III. The organic phases are combined, washed, dried, and concentrated under reduced pressure to obtain a crude product. The crude product is added to organic solvent IV, stirred at room temperature for 20-60 minutes, filtered, and the filtrate is cooled to -15°C to -5°C, stirred for 1-3 hours, filtered, the filter cake is collected, dried, and the target compound 2, namely 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane);
[0020] More preferably, the organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.
[0021] And / or the organic solvent IV is selected from one or more of isooctane, cyclohexane, hexane, petroleum ether, n-pentane, and isopentane.
[0022] The reaction is a metal halide exchange-boronization reaction, and the specific process is explained below:
[0023] Step 1: Generation of strongly alkaline organolithium reagent
[0024] At -65°C, 2,2,6,6-tetramethylpiperidine (TMPH) reacts with n-butyllithium (n-BuLi) to generate the strongly basic 2,2,6,6-tetramethylpiperidine lithium (TMPLi). This step is a typical process for preparing organolithium reagents, and TMPLi can be used as a highly efficient deprotonating or metallizing agent.
[0025] Step 2: Metal halide exchange and borylation
[0026] A key reaction occurs when brominated cyclopropane and pinacol diboronate (B2pin2) are added at low temperature: TMPLi undergoes metal halide exchange with brominated cyclopropane to generate a highly active cyclopropyl lithium intermediate.
[0027] Cyclopropyllithium immediately undergoes a borate reaction with B2pin2 to form cyclopropylpinacol boronic acid ester (the monoborate product of target compound 2).
[0028] Because bromocyclopropane contains two equivalent reaction sites, it ultimately produces a 1,1′-diboronized product (a symmetrical diboronate).
[0029] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0030] This invention provides a method for synthesizing 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-di(cyclopropane). Using bromocyclopropane as a starting material, a one-step reaction is carried out with 2,2,6,6-tetramethylpiperidine, n-butyllithium, and pinacol diboronate to obtain 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-di(cyclopropane). This method offers a concise procedure, simple operation, and relatively mild reaction conditions, yielding the target compound in high yield. It provides a potential route for the process synthesis of 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-di(cyclopropane). Attached Figure Description
[0031] Figure 1 The image shows the 1H NMR spectrum of compound 2 from Example 1. Detailed Implementation
[0032] To more fully understand and demonstrate the technical solutions, objectives, and advantages of the present invention, the technical effects produced by the present invention will be further described in detail and completely below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. It should be noted that other embodiments obtained by those skilled in the art without departing from the concept of the present invention are all within the protection scope of the present invention.
[0033] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.
[0034] Example 1
[0035] This embodiment provides a synthetic method for 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane), and the synthetic route is as follows:
[0036]
[0037] The specific steps are as follows:
[0038] (1) 2,2,6,6-Tetramethylpiperidine (280.23 g, 1.98 mol, 1.20 eq) was added to tetrahydrofuran (2.0 L) solvent. Under inert nitrogen protection, n-butyllithium solution (991.92 mL, 1.98 mol, 1.20 eq, 2 M in THF) was added dropwise at -65 °C. After the addition was complete, the temperature was naturally raised to 0 °C and reacted for 30 minutes. Then the temperature was lowered to -65 °C, and pinacol ester diboronate (419.82 g, 1.65 mol, 1.00 eq) and a tetrahydrofuran (1.0 L) solution of compound 1, namely bromocyclopropane (200.00 g, 1.65 mol, 1.00 eq) were added dropwise. The mixture was stirred at -65 °C for 1 hour, and then stirred at 25 °C for 12 hours.
[0039] (2) After the reaction was completed, water (2.0 L) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (2.0 L × 3). The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was added to petroleum ether (1.0 L), stirred at 25 °C for 30 minutes, filtered, and the filtrate was cooled to -10 °C and stirred for 2 hours. The filtrate was filtered, the filter cake was collected, and dried to obtain the target compound 2, namely 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane), with a weight of 548.90 g, a purity of 98%, and a yield of 97%.
[0040] The 1H NMR spectrum of 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane) is shown below. Figure 1 As shown, the obtained characterization data are as follows:
[0041] 1 H NMR (400MHz, CDCl3) δ1.20 (s, 24H), 0.47 (d, J = 2.2Hz, 4H), 0.14 (d, J = 2.2Hz, 4H).
[0042] Examples 2-8
[0043] Examples 2-8 are the same as Example 1, except that the amounts of 2,2,6,6-tetramethylpiperidine, n-butyllithium, pinacol diboronate, and organic solvent I used in step (1) are adjusted, as shown in Table 1. Examples 1-6 and Comparative Examples 1-2 were used to verify the effect of various reaction conditions on the reaction yield in the synthesis of intermediate 2-(2-(5-bromo-3-fluoro-2-(methoxycarbonyl)phenyl)malonate diethyl ester), and the results are shown in Table 1.
[0044] Table 1: Synthesis conditions and results of the examples
[0045]
[0046]
[0047] As can be seen from the results in Table 1, and from the results of Examples 1-3, when the molar ratio of the starting material bromocyclopropane to 2,2,6,6-tetramethylpiperidine is 1.0:1.0 to 2.5, the yield of the target compound 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane) is relatively high. Among them, the product yields are basically the same when the molar ratio of bromocyclopropane to 2,2,6,6-tetramethylpiperidine is 1.0:1.2 and 1.0:2.5.
[0048] The results from Examples 1, 4-5 show that when the molar ratio of the starting material bromocyclopropane to n-butyllithium is 1.0:1.0-2.5, the yield of the target compound 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-bis(cyclopropane) is relatively high. Among them, the product yields are basically the same when the molar ratio of bromocyclopropane to 2,2,6,6-tetramethylpiperidine is 1.0:1.2 and 1.0:2.5.
[0049] The results from Examples 1 and 6 show that the product yields are basically the same when the molar ratio of bromocyclopropane to pinacol diboronic acid is 1.0:1.0 and 1.0:2.5.
[0050] In Examples 1 and 7-8, tetrahydrofuran, n-hexane, and diethyl ether were used as solvents for the reaction, respectively. The reactions proceeded smoothly, and the yields of the target compound 1,1′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1′-di(cyclopropane) were all high. The reaction with tetrahydrofuran as the solvent yielded the highest result. The above are merely preferred embodiments of the present invention and are not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. A method for synthesizing 1,1'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1'-bis(cyclopropane), characterized in that, The type of reaction in the synthesis method is metal halide exchange-boronization reaction.
2. The method for synthesizing 1,1'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1'-bis(cyclopropane) according to claim 1, characterized in that, The synthetic route of the synthetic method is as follows:
3. The method for synthesizing 1,1'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1'-bis(cyclopropane) according to claim 2, characterized in that, Includes the following steps: (1) Add 2,2,6,6-tetramethylpiperidine to organic solvent I. Under inert gas protection, add n-butyllithium solution dropwise at -80℃ to -50℃. After the addition is complete, naturally raise the temperature to -5℃ to 5℃ and react for 20-40 minutes. Then lower the temperature to -80℃ to -50℃ and add pinacol diboronic acid ester and organic solvent II solution of compound 1, i.e. bromocyclopropane. Stir at -80℃ to -50℃ for 0.5-3 hours, and then stir at room temperature for 8-40 hours.
4. The method for synthesizing 1,1'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1'-bis(cyclopropane) according to claim 3, characterized in that, In step (1) described above, The organic solvent I is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, diethyl ether, and methyl tert-butyl ether; The organic solvent II is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane, diethyl ether, and methyl tert-butyl ether.
5. The method for synthesizing 1,1'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1'-bis(cyclopropane) according to claim 3, characterized in that, In step (1), the n-butyllithium solution is one or more of the following: n-butyllithium dissolved in n-hexane solution, n-butyllithium dissolved in n-ethane solution, and n-butyllithium dissolved in tetrahydrofuran solution.
6. The method for synthesizing 1,1'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1'-bis(cyclopropane) according to claim 3, characterized in that, In step (1) described above, The molar ratio of compound 1 to 2,2,6,6-tetramethylpiperidine is 1:1-3; The molar ratio of compound 1 to pinacol diboronate is 1:1-3; The molar ratio of compound 1 to the n-butyllithium solution is 1:1-3; The mass-to-volume ratio of compound 1 to organic solvent I is 1:5-40 g / mL; The mass-to-volume ratio of compound 1 to organic solvent II is 1:5 to 40 g / mL.
7. The method for synthesizing 1,1'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1'-bis(cyclopropane) according to claim 3, characterized in that, include: (2) After the reaction is completed, the resulting reaction solution is post-treated to obtain target compound 2, namely 1,1'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1'-bis(cyclopropane).
8. The method for synthesizing 1,1'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1'-bis(cyclopropane) according to claim 7, characterized in that, In step (2), the post-processing includes: after the reaction is completed, water is added to the reaction solution, and the solution is extracted with organic solvent III. The organic phases are combined, washed, dried, and concentrated under reduced pressure to obtain a crude product. The crude product is added to organic solvent IV, stirred at room temperature for 20-60 minutes, filtered, and the filtrate is cooled to -15°C to -5°C, stirred for 1-3 hours, filtered, the filter cake is collected, dried, and the target compound 2, namely 1,1'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1'-bis(cyclopropane), is obtained.
9. The method for synthesizing 1,1'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1'-bis(cyclopropane) according to claim 8, characterized in that, In step (2) described above, The organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane; And / or the organic solvent IV is selected from one or more of isooctane, cyclohexane, hexane, petroleum ether, n-pentane, and isopentane.