Preparation method of conjugated fluoroolefin

Abstract

The invention discloses a preparation method of conjugated fluoroolefin, and belongs to the technical field of organic chemistry. The preparation method of the conjugated fluoroolefin is based on a silicon free radical mediated yoke difluoroalkenylation strategy, and the method takes trifluoromethyl ketone as a starting material, does not need a transition metal catalyst, and generates active silicon free radicals through the synergistic effect of a silicon-boron reagent under an alkaline condition. The silicon free radicals can grab hydrogen atoms from an allyl C-H bond to form an allyl free radical intermediate, then selective fracture of a gamma-C-F bond is initiated, and finally gem-difluoro-1, 3-butadiene with a clear structure is generated. The strategy provides a brand new method path for precise synthesis of conjugated gem-difluoroolefin, and has good application prospects and theoretical values.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic chemistry, and particularly relates to a preparation method of a conjugated fluoroalkene. BACKGROUND

[0002] Due to the unique properties of fluorine-containing compounds in molecular structure, electronic effect and biological activity, the synthesis strategy has become an important direction in the research of drug chemistry and functional materials, and has attracted much attention in the academic field in recent years. The strong electronegativity and high chemical stability of fluorine atoms significantly improve the comprehensive performance of fluorine-containing compounds in stability, fat solubility and biological activity, and thus are widely used in drug molecule design, high-performance polymer synthesis and development of new environmentally friendly materials, showing irreplaceable application potential. Among them, gem-difluoro conjugated diene is a multifunctional synthetic building block, and is an important intermediate for constructing natural products and functional molecules containing gem-difluoromethyl groups. Therefore, the efficient synthesis of such fluorine-containing compounds is of great significance for promoting the precise construction of fluorine-containing molecules and their application in life science and material science.

[0003] In traditional synthesis methods, the construction of fluorinated 1,3-diene mainly relies on Wittig olefination and transition metal-catalyzed coupling reactions. These methods can achieve the synthesis of target products under specific conditions, but generally have problems such as high requirements for substrate functionalization, harsh reaction conditions, expensive catalysts or environmental unfriendliness. In addition, due to the unique electronegativity and spatial effect of fluorine atoms, their introduction often has a significant impact on the reaction path and intermediate stability, making traditional methods face many limitations in practical application. Although in recent years, various alternative strategies have been reported, such as rearrangement reactions based on fluorinated alkenes, radical pathways, and photocatalytic methods, there are still key problems such as insufficient stereoselectivity control, difficulty in accurately adjusting regioselectivity, and complicated synthesis steps of fluorinated functional groups, which need to be systematically studied in terms of reaction mechanism, catalyst system design and synthesis strategy optimization, in order to realize more efficient, greener and more universal synthesis methods of fluorinated 1,3-diene.

[0004] In recent years, important progress has been made in the study of functionalization methods of fluorine-containing groups, especially the strategy based on selective C-F bond cleavage can efficiently convert cheap and readily available CF3 compounds into difluoroalkylated products, providing new ideas and means for the diversity synthesis of fluorine-containing compounds. The stepwise removal of fluorine atoms weakens the C-F bond strength, providing an opportunity for further conversion of fluorine-containing groups. However, there is still a lack of a general, efficient and stereoselective synthetic strategy to achieve efficient construction of fluorinated 1,3-diene through C-F bond cleavage. Therefore, developing a simple and selective synthetic method has important innovative significance for breaking through the bottleneck of controllable synthesis of fluorinated conjugated diene compounds. SUMMARY

[0005] In view of the above prior art, the present application provides a preparation method of conjugated fluorinated olefin to solve the technical problems of difficult preparation and high cost of gem-difluoro conjugated diene in the prior art.

[0006] In order to achieve the above purpose, the technical scheme adopted by the present application is to provide a preparation method of conjugated fluorinated olefin, comprising the following steps: S1: dissolving fluorinated alkyl ketone and benzenesulfonyl hydrazine in a solvent, stirring at room temperature for 3-5 h to obtain an intermediate product; the structural formula of the fluorinated alkyl ketone is shown as formula I,

[0007] wherein R1 is at least one of hydrogen, alkoxy and halogen; R2 is fluorine, methoxy or halogenated alkyl; S2: dissolving the base, silicon boron reagent and the intermediate product in dioxane from which the stabilizer has been removed, and then stirring at 95-110 DEG C for 2-5 h to obtain a crude product; the liquid ratio of the base, silicon boron reagent, intermediate product and dioxane from which the stabilizer has been removed is 3.3 mol:3 mol:1 mol:5 L; S3: column chromatography elution is performed on the crude product to obtain the conjugated fluorinated olefin shown as formula II, .

[0008] The present application uses cheap and readily available trifluoromethyl ketone as a starting substrate, without the need for transition metal catalysts, and through the synergistic effect of silicon boron reagent under basic conditions, active silicon free radicals are efficiently generated. The substrate has wide applicability, the aromatic ring can be modified with alkyl or halogen, and the trifluoromethyl group can be further converted into more complex fluorinated compounds.

[0009] It is worth noting that the product will be significantly different under different proportions of alkali and silicon-boron reagent. When the equivalent ratio of intermediate product, sodium tert-butoxide and silicon-boron reagent is 1:3.3:3, it is most beneficial to the generation of gem-difluoro conjugated diene. This is because under this proportion, the silicon radical intermediate can be efficiently generated in the reaction system, and the breakage of the γ-C-F bond is induced through its unique reaction path, thereby dominating the formation of gem-difluoro conjugated diene. Specifically, sodium tert-butoxide not only promotes the deprotonation of hydrazone in the reaction, but also can induce the single electron transfer (SET) process of the silicon-boron reagent through the synergistic effect, thereby generating a highly active silicon radical. The silicon radical has a low charge density and a high nucleophilicity, and can react with the carbon atom of the trifluoromethyl group, so that the C-F bond breaks under the radical mechanism. This process is different from the traditional nucleophilic substitution or elimination mechanism, but through the radical-induced rearrangement or migration path, the precursor structure of gem-difluoro conjugated diene is formed.

[0010] Under the condition of the equivalent ratio of 1:3.3:3, the equivalent of the silicon-boron reagent is relatively high, which is beneficial to generate a sufficient amount of silicon radical. The high concentration of silicon radical is helpful to form a stable carbon radical intermediate, which is more likely to construct the conjugated diene structure in the subsequent fluorination and rearrangement process. Therefore, the equivalent ratio of 1:3.3:3 induces the breakage of the γ-C-F bond through the efficient generation and stable existence of the silicon radical, and further realizes the high-selective synthesis of gem-difluoro conjugated diene through the radical rearrangement and conjugation expansion mechanism. This ratio not only optimizes the thermodynamic and kinetic conditions of the reaction path, but also provides important experimental basis and theoretical guidance for the stereoselectivity and structural diversity of trifluoroalkene.

[0011] Based on the above technical solutions, the application can be further improved as follows.

[0012] Further, the feed liquid ratio of the fluorinated alkyl ketone, the benzene sulfonyl hydrazine and the solvent is 1 mol:0.8-1.2 mol:5 L.

[0013] Further, the fluorinated alkyl ketone is one of the compounds with the following structure: 、 、 、 .

[0014] Further, the benzene sulfonyl hydrazine is 2-(trifluoromethyl) benzene sulfonyl hydrazine, and the solvent is methanol.

[0015] Further, the alkali is sodium tert-butoxide, and the silicon-boron reagent is SiEt3-Bpin.

[0016] Further, the method for removing dioxane stabilizer is as follows: mixing bulk sodium with dioxane, then heating the mixture to 100 DEG C, and refluxing for 3 hours, and collecting the distilled dioxane to obtain the product.

[0017] Further, the stirring reaction temperature in S2 is 100 DEG C, and the stirring reaction time is 3 hours.

[0018] Further, the eluent used in the column chromatography in S3 is n-hexane.

[0019] The present application has the following advantages: The preparation process of the conjugated fluoroalkene in the present application is shown in Figure 1 The preparation method of the conjugated fluoroalkene is based on a silicon radical-mediated di-fluoroalkenylation strategy. The method uses a trifluoromethyl ketone as a starting material, does not need a transition metal catalyst, and generates active silicon radicals through the synergistic effect of a silicon boron reagent under alkaline conditions. These silicon radicals can capture hydrogen atoms from an allyl C-H bond to form an allyl radical intermediate, and then initiate the selective cleavage of a gamma-C-F bond to finally generate a well-defined gem-difluoro-1,3-butadiene. This strategy provides a new method path for the precise synthesis of conjugated gem-difluoroalkenes, and has good application prospect and theoretical value. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 The preparation process of the conjugated fluoroalkene in the present application is shown in Figure 2 The preparation process of the conjugated fluoroalkene in Example 1 is shown in Figure 3 The preparation process of the conjugated fluoroalkene in Example 2 is shown in Figure 4 The preparation process of the conjugated fluoroalkene in Example 3 is shown in Figure 5 The preparation process of the conjugated fluoroalkene in Example 4 is shown in DETAILED DESCRIPTION

[0021] The specific embodiments of the present application will be described in detail below with reference to the examples.

[0022] Example 1 A preparation method of a conjugated fluoroalkene, and the preparation process is shown in Figure 2 The method specifically comprises the following steps: (1) In a 10 mL round bottom flask with a magnetic stir bar, 1,1,1-trifluoro-4- phenylbutan-2-one 202.6 mg (1.0 eq) and 2-(trifluoromethyl)benzenesulfonyl hydrazide 218.2 mg (0.9 eq) were added to methanol (5 mL) and dissolved thoroughly, the reaction was stirred continuously at room temperature for 4 h; then the reaction solution was spin dried and recrystallized in n-hexane to obtain hydrazone 1a as a white solid with a yield of 89%. The hydride spectrum data of 1a is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.33 - 8.24 (m, 1H), 7.95 (s, 1H), 7.90 -7.83 (m, 1H), 7.81 - 7.70 (m, 2H), 7.34 - 7.23 (m, 3H), 7.17 (d, J = 7.2 Hz,2H), 2.82 (t, J = 7.9 Hz, 2H), 2.60 (t, J = 7.9 Hz, 2H)。

[0023] (2) Cut 3 g of sodium metal into small pieces (50 mg / piece) and place in a 1 L flask, add 500 mL of dioxane, then reflux at 100 °C for 3 h, collect the distilled dioxane, and store it in a sealed container. The main purpose of this operation is to remove the stabilizer BHT to prevent it from generating free radicals to interfere with the reaction process.

[0024] (3) Put a 5 mL glass bottle with a magnetic stir bar into a glove box, add sodium tert-butoxide 28.8 mg (3.3 eq), SiEt3-Bpin 114 mg (3.0 eq), and 1a 44.2 mg (1.0 eq); then add 0.5 mL of dioxane treated in step (2) with a syringe and dissolve thoroughly.

[0025] (4) Take the glass bottle out of the glove box and put it into a 100 °C constant temperature stirrer to stir for 3 h.

[0026] (5) Take the glass bottle out of the constant temperature stirrer and elute it by flash column chromatography (eluent: n-hexane) to obtain clear colorless oil 13.28 mg, which is conjugated fluoroalkene (2a) with a yield of 80%. The characterization spectrum data of 2a is as follows: 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 7.6 Hz, 2 H), 7.30 (t, J = 7.2 Hz,2 H), 7.21 (t,J = 7.2 Hz, 1 H), 6.65 (dd, J = 16.0 Hz, 10.8 Hz, 1 H), 6.44 (d, J =15.6 Hz, 1 H), 5.10 (dd, J = 24.0 Hz, 10.8 Hz, 1 H). 19 F NMR (376 MHz, CDCl3) δ -85.3 (d, J = 26.3 Hz, 1 F), -87.0 (d, J = 30.1Hz, 1 F). Example 2 A method for preparing conjugated fluoroolefins, the preparation process is as follows Figure 3 As shown; specifically including the following steps: (1) In a 10 mL round-bottom flask equipped with a magnetic stirrer, 266.7 mg (1.0 equivalent) of 4-(3-chloro-4-methoxyphenyl)-1,1,1-trifluorobutan-2-one and 218.2 mg (0.9 equivalent) of 2-(trifluoromethyl)benzenesulfonylhydrazide were added and fully dissolved in methanol (5 mL). The mixture was stirred continuously at room temperature for 4 h. The reaction solution was then dried and recrystallized from n-hexane to obtain intermediate 1b. (2) Cut 3 g of sodium metal into small pieces (50 mg / piece) and place them in a 1 L flask. Add 500 mL of dioxane and reflux at 100 °C for 3 h. Collect the distilled dioxane and seal it for storage. The main purpose of this operation is to remove the stabilizer BHT and prevent it from generating free radicals that interfere with the reaction process.

[0027] (3) Place a 5 mL glass bottle with a magnetic stirrer in a glove box and add 28.8 mg (3.3 equivalents) of sodium tert-butoxide, 114 mg (3.0 equivalents) of SiEt3-Bpin, and 48.8 mg (1.0 equivalents) of 1b; then, add 0.5 mL of dioxane treated in step (2) using a syringe and dissolve thoroughly; (4) Take the glass bottle out of the glove box and place it in a constant temperature stirrer at 100°C for 3 h; (5) The glass bottle was removed from the thermostatic stirrer and eluted by flash column chromatography (eluent: n-hexane) to obtain 12.65 mg of a clear, colorless oil, i.e., conjugated fluoroolefin (2b), in a 55% yield. The characterization chromatographic data of 2b are as follows: 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1 H) 7.21 (d, J = 8.4 Hz 1 H), 6.86(d, J = 8.4 Hz, 1 H), 6.52 (dd, J = 15.6 Hz, 10.8 Hz, 1 H), 6.34 (d, J = 15.6 Hz, 1H), 5.10 (dd, J = 24.0 Hz, 10.8 Hz, 1 H), 3.90 (s, 3 H). 19 F NMR (376 MHz, CDCl3) δ -85.3 (d, J = 26.3 Hz, 1 F), -87.1 (d, J = 26.3Hz, 1 F). Example 3 A method for preparing a conjugated fluoroalkene, the preparation flow is shown as Figure 4 Specifically comprising the following steps: (1) In a 10 mL round-bottom flask with a magnetic stirrer, 1,1,1,2,2-pentafluoro-5- phenylpentan-3-one 252.2 mg (1.0 equivalent) and 2-(trifluoromethyl)benzenesulfonyl hydrazide 218.2 mg (0.9 equivalent) were added to a solution in methanol (5 mL) and dissolved thoroughly, and then the reaction was continuously stirred at room temperature for 4 h; then the reaction solution was spin-dried and recrystallized in n-hexane to obtain intermediate 1c; (2) 3 g of sodium metal was cut into small pieces (50 mg / piece) and placed in a 1 L flask, 500 mL of dioxane was added, and then refluxed at 100°C for 3 h, the distilled dioxane was collected and stored in a sealed container, and the main purpose of this operation was to remove the stabilizer BHT to prevent it from generating free radicals to interfere with the reaction process.

[0028] (3) A 5 mL glass bottle with a magnetic stirrer was placed in a glove box, sodium tert-butoxide 28.8 mg (3.3 equivalent), SiEt3-Bpin 114 mg (3.0 equivalent) and 1c 47.4 mg (1.0 equivalent) were added; then 0.5 mL of dioxane treated in step (2) was added with a syringe and dissolved thoroughly; (4) The glass bottle was taken out of the glove box and placed in a 100°C constant temperature stirrer for stirring reaction for 3 h; (5) The glass bottle was removed from the thermostatic stirrer and eluted by flash column chromatography (eluent: n-hexane) to obtain 8.6 mg of a clear, colorless oil, namely, conjugated fluoroolefin (2c), in a 40% yield. The characterization chromatographic data of 2c are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.2 Hz, 2 H), 7.39-7.30 (m, 3 H), 6.97 (dd, J = 16.0 Hz, 11.2 Hz, 1 H), 6.80 (d, J = 15.6 Hz, 1 H), 6.25 (dd, J =31.6 Hz, 10.8 Hz, 1 H). 19 F NMR (376 MHz, CDCl3) δ -71.9 (d, J = 11.3 Hz, 3 F), -134.5 (q, J =11.3 Hz, 1 F). Example 4 A method for preparing conjugated fluoroolefins, the preparation process is as follows Figure 5 As shown; specifically including the following steps: (1) In a 10 mL round-bottom flask equipped with a magnetic stirrer, 302.2 mg (1.0 equivalent) of 4,4,5,5,6,6,6-heptafluoro-1-phenylhexan-3-one and 218.2 mg (0.9 equivalent) of 2-(trifluoromethyl)benzenesulfonylhydrazide were added and fully dissolved in methanol (5 mL). The mixture was stirred continuously at room temperature for 4 h. The reaction solution was then dried and recrystallized from n-hexane to obtain intermediate 1d. (2) Cut 3 g of sodium metal into small pieces (50 mg / piece) and place them in a 1 L flask. Add 500 mL of dioxane and reflux at 100 °C for 3 h. Collect the distilled dioxane and seal it for storage. The main purpose of this operation is to remove the stabilizer BHT and prevent it from generating free radicals that interfere with the reaction process.

[0029] (3) Place a 5 mL glass bottle with a magnetic stirrer in a glove box and add 28.8 mg (3.3.0 equivalents) of sodium tert-butoxide, 114 mg (3.0 equivalents) of SiEt3-Bpin, and 52.4 mg (1.0 equivalents) of 1d; then, add 0.5 mL of dioxane treated in step (2) using a syringe and dissolve thoroughly; (4) Take the glass bottle out of the glove box and place it in a constant temperature stirrer at 100°C for 3 h; (5) The glass bottle was removed from the constant temperature stirrer and eluted by flash column chromatography (eluent: n-hexane) to obtain 18.0 mg of clear colorless oil, conjugated fluoroolefin (2d), in a yield of 63%. The characterization spectrum data of 2d are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 6.8 Hz, 2 H), 7.40-7.31 (m, 3 H),7.01 (dd, J = 16.0 Hz, 11.2 Hz, 1 H), 6.82 (d, J = 15.6 Hz, 1 H), 6.25 (dd, J = 32.0 Hz, 11.2 Hz, 1 H). 13 C NMR (101 MHz, CDCl3) δ 144.5 (dt, J = 263.0 Hz, 29.0 Hz), 140.6 (dd, J = 221.0 Hz, 10.0 Hz), 138.5 (d, J = 4.0 Hz), 135.8, 129.1, 128.8, 127.1, 118.5(dd, J = 248.0 Hz, 37.0 Hz), 116.9, 114.8 (q, J = 5.0 Hz). Although the specific embodiments of the present application are described in detail with reference to the embodiments, it should not be understood as limiting the scope of protection of the patent. Various modifications and variations that can be made by those skilled in the art without creative labor within the scope described in the claims are still within the scope of protection of the patent.

Claims

1. A method for preparing a conjugated fluoroolefin, characterized in that: The following steps are involved: S1: Dissolve the fluoroalkyl ketone and benzenesulfonyl hydrazide in a solvent, and stir the mixture at room temperature for 3 to 5 hours to obtain an intermediate product; the structural formula of the fluoroalkyl ketone is shown in Formula I. wherein R1 is at least one of hydrogen, alkoxy and halogen; R2 is fluorine, methoxy or haloalkyl; S2: Dissolve the base, borosilicate reagent, and intermediate product in dioxane after the stabilizer has been removed, and then stir and react at 95-110° C. for 2-5 hours to obtain a crude product; the material-liquid ratio of the base, borosilicate reagent, intermediate product, and dioxane after the stabilizer has been removed is 3.3 mol:3 mol:1 mol:5 L; S3: The crude product is subjected to column chromatography to obtain a conjugated fluoroolefin as shown in Formula II. 。 2. The preparation method according to claim 1, wherein: The material-liquid ratio of the fluoroalkyl ketone, benzenesulfonyl hydrazide and solvent is 1 mol:0.8~1.2 mol:5L.

3. The preparation method according to claim 1 or 2, characterized in that The fluoroalkyl ketone is one of the compounds having the following structure: 、 、 、 。 4. The preparation method according to claim 1 or 2, characterized in that: The benzenesulfonyl hydrazide is 2-(trifluoromethyl)benzenesulfonyl hydrazide; and the solvent is methanol.

5. The preparation method according to claim 1, wherein: The base is sodium tert-butoxide.

6. The preparation method according to claim 1, wherein: The silicon boron reagent is SiEt3-Bpin.

7. The preparation method according to claim 1 or 5, characterized in that The method for removing the stabilizer by using dioxane is as follows: mixing bulk sodium metal with dioxane, then heating the mixture to 100° C., keeping the mixture under reflux for 3 hours, and collecting the dioxane distilled to obtain the product.

8. The preparation method according to claim 1, wherein: The stirring reaction temperature in S2 is 100° C., and the stirring reaction time is 3 h.

9. The preparation method according to claim 1, wherein: The eluent used for column chromatography elution in S3 was n-hexane.

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