Preparation method of fluoroolefin

Abstract

The invention discloses a preparation method of fluoroolefin, and belongs to the technical field of organic chemistry. The preparation method of the fluoroolefin is based on a silicon free radical mediated trifluoromethylation strategy, a SiEt3-Bpin silane reagent is used as a silicon free radical source, a transition metal catalyst is not needed, and potential harm of metal to the environment is effectively avoided. Meanwhile, by directly using the fluoroalkyl ketone which is low in price and easy to obtain as the starting substrate, the complex functionalization step in the traditional trifluoromethylation process is simplified. In addition, the silicon free radical mediated trifluoromethyl hydrazone realizes efficient synthesis of fluorine-containing olefin with single configuration in the double bond migration process, and a novel green, efficient and universal method is provided for construction of fluoroolefin with high trans-selectivity.

Description

TECHNICAL FIELD

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

[0002] The fluorine atom has the strongest electronegativity among all elements, and its van der Waals radius is only second to that of the hydrogen atom, so that the C-F bond has a highly polarized characteristic, a short bond length, and an electron cloud tightly attracted by the fluorine nucleus, showing a low polarizability. These unique physical and chemical properties significantly affect the physical, chemical, and biological behaviors of fluorine-substituted or fluorine alkyl-substituted organic compounds, making them irreplaceable in the optimization of polymer material performance and the design of drug molecules. Among them, trifluoromethyl olefins are an important class of fluorine-containing compounds. Studies have shown that the introduction of a trifluoromethyl group into a small molecule drug can effectively prolong its action time in the body, thereby improving the bioavailability and therapeutic effect of the drug (such as Fludelone). In addition, the trifluoromethyl functional group has high lipophilicity, which helps to improve the cell membrane permeability and pharmacokinetic properties of the drug molecule. At the same time, trifluoromethyl olefins have gradually developed into new trifluoromethylation reagents due to their good atom economy and reactivity. Therefore, developing an efficient and controllable synthesis method of trifluoromethyl olefin compounds is of great significance for promoting the application of fluorine chemistry in life sciences and material sciences.

[0003] Although there are currently various methods for the synthesis of fluorine-containing olefins, there are still many limitations in reaction conditions, substrate scope, and control of regioselectivity and stereoselectivity. Especially in the construction of fluorine-containing olefins with clear configuration, existing synthesis strategies often have difficulty in achieving precise control. At present, the construction of olefin structures with a double bond position determined mainly relies on classical Wittig reaction, Julia-Kocienski reaction, and Horner-Wadsworth-Emmons (HWE) reaction. However, these methods have limited control ability in the synthesis of single configuration fluorine-containing olefins, and in the process of participating in Wittig reaction, etc., they are easy to generate difluorocarbene intermediates, and even initiate single electron transfer process, leading to the difference in reaction mechanism from the traditional double electron path synthesis of cis non-fluorine olefins.

[0004] In recent years, transition metal-catalyzed (such as Cu, Pd, Ni) Heck-type trifluoromethylation reactions have been widely used. Although significant progress has been made in this field, the substrate range is still limited, mainly applicable to styrene compounds. In addition, the transition metal catalytic system is often accompanied by metal residue problems, and such reactions are accompanied by the generation of perfluoride or silicon-based by-products, which affect the purity of the product and limit its promotion in green chemistry. In addition, visible light-induced terminal olefin trifluoromethylation reactions have made significant progress, and by using photosensitizers (such as Ru(Phen)3Cl3, Ir(ppy)2, etc.) to generate free radicals under visible light irradiation, the introduction of trifluoromethyl on the terminal olefin is realized. However, this method still faces certain challenges in practical application, which may cause olefin isomerization during the reaction process, resulting in poor E / Z selectivity of the product, and the cost of metal photocatalysts is high, and the light-sensitive substrate needs to be strictly protected from light during storage and transportation, which limits its wide application in industrial production and drug synthesis. SUMMARY

[0005] In view of the above prior art, the present application provides a preparation method of fluoroalkene to solve the technical problems of difficult preparation and high cost of fluoroalkene 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 fluoroalkene, comprising the following steps: S1: co-dissolve fluoroalkyl ketone and benzenesulfonyl hydrazine in a solvent, stir at room temperature for 3-5 h to obtain an intermediate product; the structural formula of the fluoroalkyl ketone is shown as formula I,

[0007] wherein R1 is a benzene-substituted alkyl or a halogenated alkyl; R2 is fluorine, methoxy or a halogenated alkyl; S2: co-dissolve the base, silicon boron reagent and intermediate product in dioxane after removing the stabilizer, then stir at 95-110℃ for 2-5 h to obtain a crude product; the liquid ratio of base, silicon boron reagent, intermediate product and dioxane after removing the stabilizer is 1 mol:2 mol:1 mol:5 L; S3: column chromatography elution is performed on the crude product to obtain fluoroalkene as shown in formula II, .

[0008] In the present application, the equivalent ratio of the intermediate, the base and the silyl-boron reagent is strictly controlled as 1:1:2. Under this condition, the reaction mechanism is through base-promoted deprotonation and nucleophilic addition elimination path, instead of relying on silicon radical-initiated C-F bond cleavage process. Under the condition of 1:1:2 ratio, the base can effectively remove the hydrogen at the α-position of the hydrazone to generate an enolate intermediate; the intermediate then reacts with the silyl-boron reagent to form a transition state or intermediate, which further undergoes rearrangement of a carbene species, and finally leads to the generation of fluorinated olefins. Unlike the silicon radical mechanism, the carbene mechanism generally involves a more nucleophilic and structurally stable transition state, and has higher stereoselectivity, thereby avoiding the complex radical rearrangement path. Using the feeding ratio in the present application, the initiation of the radical path is inhibited, while sufficient silyl-boron reagent is provided to promote the formation and conversion of the carbene intermediate, thereby ensuring that the reaction proceeds efficiently along the carbene path.

[0009] In addition, under this ratio, the equivalent of the base is 1, which is sufficient to complete the deprotonation of the hydrazone without initiating excessive deprotonation, thereby avoiding the occurrence of side reactions (such as excessive elimination or formation of non-target structures). The equivalent of the silyl-boron reagent is 2, which provides sufficient fluorine source and ligand stability to support the generation and subsequent conversion of the carbene intermediate. The precise control of this ratio enables the reaction system to efficiently lead to the generation of trifluorinated olefins and improve their yield and selectivity.

[0010] In summary, the present application controls the equivalent ratio of the intermediate, the base and the silyl-boron reagent as 1:1:2, and through the synergistic effect of the base and the silyl-boron reagent, the dominant position of the carbene conversion mechanism is promoted, and the silicon radical-initiated C-F bond cleavage path is avoided. This ratio not only optimizes the thermodynamic and kinetic conditions of the reaction, but also provides important experimental basis and theoretical guidance for the efficient synthesis of fluorinated olefins.

[0011] On the basis of the above technical solutions, the present application can also be improved as follows.

[0012] Further, the 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 having the following structure: 、 、 、 、 .

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

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

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

[0017] Further, the stirring reaction temperature in S2 is 100℃, and the stirring reaction time is 3h.

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

[0019] The beneficial effects of the present application are as follows: The preparation process of the fluoroalkene in the present application is as shown in Figure 1 The preparation method of the fluoroalkene is based on a silicon radical-mediated trifluoromethylation strategy, and uses SiEt3-Bpin silane reagent as a silicon radical source, without the need for a transition metal catalyst, effectively avoiding the potential harm of metals to the environment. At the same time, by directly using a fluorinated alkyl ketone with low price and easy to obtain as a starting material, the complex functionalization step in the traditional trifluoromethylation process is simplified. In addition, the silicon radical-mediated trifluoromethyl hydrazone realizes the efficient synthesis of a single configuration of the fluoroalkene in the process of double bond migration, providing a green, efficient and universal new method for the construction of high-trans-selective fluoroalkene. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 The preparation process of the fluoroalkene in the present application is as shown in Figure 2 The preparation process of the fluoroalkene in Example 1 is as shown in Figure 3 The preparation process of the fluoroalkene in Example 2 is as shown in Figure 4 The preparation process of the fluoroalkene in Example 3 is as shown in Figure 5 The preparation process of the fluoroalkene in Example 4 is as shown in Figure 6 The preparation process of the fluoroalkene in Example 5 is as shown in DETAILED DESCRIPTION

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

[0022] Example 1 A preparation method of a fluoroalkene, the preparation process is as shown in Figure 2 The specific steps are as follows: (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 white solid hydrazone 1a with a yield of 89%. The hydrazones 1a had the following spectroscopic data: 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 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 8 mL glass bottle with a magnetic stir bar into a glove box, add sodium tert-butoxide 9.6 mg (1.0 eq), SiEt3-Bpin 76 mg (2.0 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 constant temperature stirrer at 100 °C and stir for 3 h.

[0026] (5) Take the glass bottle out of the constant temperature stirrer and elute by flash column chromatography (eluent: n-hexane) to obtain clear colorless oil 19 mg, i.e. trifluoromethyl olefin (2a), with a yield of 93%. The characterization spectrum data of 2a are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.2 Hz, 2 H), 7.25 (t, J = 6.8 Hz,1 H), 7.16 (t, J= 7.6 Hz, 2 H), 6.57-6.49 (m, 1 H), 5.63-5.54 (m, 1 H), 3.46-3.45 (m, 2 H). 19 F NMR (376 MHz, CDCl3) δ -63.9 (s, 3 F)。

[0027] Example 2 A method for preparing a fluoroalkene, the preparation flow is shown as Figure 3 Specifically comprising the following steps: (1) In a 10 mL round-bottom flask with a magnetic stirrer, 7-bromo-1,1,1- trifluoro-2-heptanone 247.1 mg (1.0 equivalent) and 2-(trifluoromethyl) benzene sulfonyl 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 1b; (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) An 8 mL glass bottle with a magnetic stirrer was placed in a glove box, and sodium tert-butoxide 9.6 mg (1.0 equivalent), SiEt3-Bpin 76 mg (2.0 equivalent) and 1b 42.4 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 taken out of the constant temperature stirrer, and clear colorless oil 15.4 mg of trifluoromethyl alkene (2b) was obtained by fast column chromatography elution (eluent: n-hexane), and the yield was 67%. The characterization spectrum data of 2b are as follows: 1 H NMR (400 MHz, CDCl3) δ 6.41-6.33 (m, 1 H), 5.68-5.59 (m, 1 H), 3.42(t, J = 6.4 Hz, 2 H), 2.22-2.17 (m, 2 H), 1.92-1.85 (m, 2 H), 1.65-1.58 (m, 2H). 19F NMR (376 MHz, CDCl3) δ -64.0 (s, 3 F).

[0029] Example 3 A method for preparing a fluoroolefin, 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.

[0030] (3) An 8 mL glass bottle with a magnetic stirrer was placed in a glove box, and sodium tert-butoxide 9.6 mg (1.0 equivalent), SiEt3-Bpin 76 mg (2.0 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 taken out of the constant-temperature stirrer, and clear colorless oil 13.2 mg of trifluoromethyl olefin (2c) was obtained by fast column chromatography elution (eluent: n-hexane), and the yield was 56%. The characterization spectrum data of 2c are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.33 (t, J = 7.6 Hz, 2 H), 7.26 (t, J = 6.8 Hz,1 H), 7.16 (d, J = 7.6 Hz, 2 H), 6.62-6.55 (m, 1 H), 5.58 (q, J = 12.0 Hz, 1 H),3.52-3.51 (m, 2 H). 19 F NMR (376 MHz, CDCl3) δ -115.2 (t, J= 3.76 Hz, 3 F), -85.3 (d, J =3.76 Hz, 2 F).

[0031] Example 4 A method for preparing a fluoroolefin, the preparation flow is shown as Figure 5 Specifically comprising the following steps: (1) In a 10 mL round-bottom flask with a magnetic stirrer, 4,4,5,5,6,6,6-heptafluoro-1- phenylhexan-3-one 302.2 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 1d; (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.

[0032] (3) An 8 mL glass bottle with a magnetic stirrer was placed in a glove box, and sodium tert-butoxide 9.6 mg (1.0 equivalent), SiEt3-Bpin 76 mg (2.0 equivalent), and 1d 52.4 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 taken out of the constant temperature stirrer, and clear colorless oil 18.0 mg of trifluoromethyl olefin (2d) was obtained by fast column chromatography elution (eluent: n-hexane), and the yield was 63%. The characterization spectrum data of 2d are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.33 (t, J = 7.2 Hz, 2 H), 7.26 (t, J = 7.2 Hz,1 H), 7.16 (d, J = 7.6 Hz, 2 H), 6.61-6.53 (m, 1 H), 5.60 (q, J = 12.0 Hz, 1 H),3.54-3.52 (m, 2 H). 19F NMR (376 MHz, CDCl3) δ -127.9 (s, 3 F), -112.5 (t, J = 3.76 Hz, 3F), -80.4 (d, J = 3.76 Hz, 2 F)。

[0033] Example 5 A method for preparing a fluoroolefin, the preparation flow is shown as Figure 6 Specifically comprising the following steps: (1) In a 10 mL round-bottom flask with a magnetic stirrer, 1,1-difluoro-1- methoxy-4-phenylbutan-2-one 216.2 mg (1.0 equivalent) and 2-(trifluoromethyl) benzene sulfonyl 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 1e; (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.

[0034] (3) An 8 mL glass bottle with a magnetic stirrer was placed in a glove box, and sodium tert-butoxide 9.6 mg (1.0 equivalent), SiEt3-Bpin 76 mg (2.0 equivalent), and 1e 43.6 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 taken out of the constant temperature stirrer, and clear colorless oil 5.9 mg of trifluoromethyl olefin (2c) was obtained by fast column chromatography elution (eluent: n-hexane), and the yield was 30%. The characterization spectrum data of 2e are as follows: 1 H NMR (400 MHz, CDCl3) 7.30 (t, J = 7.6 Hz, 2 H), 7.26 (q, J = 7.6 Hz, 3H), 6.40-6.33 (m, 1 H), 5.87 (d, J = 11.6 Hz, 1 H), 4.03 (d, J = 7.6 Hz, 2 H),3.75 (s, 3 H). 19 F NMR (376 MHz, CDCl3) δ -58 (d, J = 1.9 Hz, 2 F).

[0035] While the present application has been described in detail with respect to specific embodiments thereof, it will be apparent to those skilled in the art that various modifications and alterations can be made without departing from the scope of the patent.

Claims

1. A method for preparing fluoroolefins, 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 a benzene-substituted alkyl group or a halogenated alkyl group; R2 is a fluorine group, a methoxy group or a halogenated alkyl group; S2: Dissolve the base, the borosilicate reagent, and the 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, the borosilicate reagent, the intermediate product, and the dioxane after the stabilizer has been removed is 1 mol:2 mol:1 mol:5 L; S3: The crude product is subjected to column chromatography to obtain a 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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