A method for preparing a fluorine-containing phenylalkane compound

Abstract

This invention discloses a method for preparing fluorophenylethane compounds, belonging to the field of organic chemical synthesis technology. The preparation method includes the following steps: mixing a photocatalyst 4CzIPN, a solvent DCE, a reducing agent DIPEA, and a reaction substrate, reacting them under blue light irradiation in a sulfur hexafluoride gas atmosphere; the reaction substrate is a compound with the structural formula [insert structural formula here], where R is H, an alkoxy group, or a cyano group. Beneficial effects: This invention uses sulfur hexafluoride as the fluorinating agent, selects a certain ratio of raw materials and catalyst, and efficiently prepares fluorophenylethane compounds. The reaction raw materials are inexpensive, the preparation process is safe and mild, has good substrate compatibility, and improves preparation efficiency.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and specifically to a method for preparing fluorophenylethane compounds. Background Technology

[0002] In 2003, German patent DE10220901A1 used the strong reducing agent tetra(trimethylamino)ethylene to activate sulfur hexafluoride gas and applied it to the dehydroxylation and fluorination conversion of alcohols. This invention can directly convert and utilize sulfur hexafluoride, but the strong reducing agent tetra(trimethylamino)ethylene is expensive (approximately 700 RMB / g), requires the use of liquid nitrogen, and poses an explosion risk due to increased internal pressure after the test tube returns to room temperature. Furthermore, the use of the solvent N,N-dimethylformamide is detrimental to the separation and purification of the product.

[0003] In 2016, TF Jamison et al. achieved the dehydroxylation fluorination of allyl alcohols using sulfur hexafluoride as the fluorinating agent under 450 nm blue-violet light irradiation. The reaction yielded good to moderate yields with good chemoselectivity, a linear-to-branch ratio as high as 11.3:1, and tolerance to a variety of functional groups (TF Jamison, Angew. Chem. Int. Ed., 2016, 55, 15072). However, this system requires an expensive iridium photocatalyst, and the substrate range is limited to allyl alcohols.

[0004] In 2017, M. Rueping et al. developed a method for reduction at room temperature using 4,4′-bipyridine-based organic two-electron donor sulfur hexafluoride (M. Rueping, Green Chem., 2017, 19, 2571). This method can generate a bipyridine dication-SF5- solid ion pair within minutes, which can be used as a powerful fluorinating agent for the deoxyfluorination of alcohols, aldehydes, and carboxylic acids. However, its main drawback is that the organic two-electron donor used has extremely strong reducing properties and is unstable, and it requires the use of metallic sodium for synthesis.

[0005] In 2021, P. Nagorny et al. reported a method for synthesizing fluoroglycosides using 4,4′-dimethoxybenzophenone as an organic photocatalyst under 365 nm ultraviolet light irradiation with sulfur hexafluoride (P. Nagorny, Org. Lett., 2021, 23, 190). They achieved yields of 43%–97% for 16 different glycoside fluorides, suggesting that the reaction may proceed via an in-situ generated SF4 intermediate, and that this species does not accumulate during the reaction. The drawbacks of this system are the requirement for high-energy ultraviolet light, a photocatalytic dosage of only 30% equivalent, and a limitation to hemiacetal structures as substrates. Summary of the Invention

[0006] The technical problem to be solved by this invention is how to solve the problems of cumbersome steps and low yield in the existing preparation process of fluorinated phenylethane compounds.

[0007] The present invention solves the above-mentioned technical problems through the following technical means:

[0008] This invention proposes a method for preparing fluorinated phenylethane compounds, comprising the following steps:

[0009] The photocatalyst 4CzIPN, solvent DCE, reducing agent DIPEA, and reaction substrate were mixed and reacted under blue light irradiation in a sulfur hexafluoride gas atmosphere. The reaction substrate has the following structural formula: Compounds in which R is H, alkoxy, or cyano.

[0010] Note: The Chinese name of 4CzIPN is 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile; the Chinese name of DCE is 1,2-dichloroethane; and the Chinese name of DIPEA is N,N-diisopropylethylamine.

[0011] Beneficial effects: This invention uses sulfur hexafluoride as a fluorinating agent and selects a certain ratio of raw materials and catalysts to efficiently prepare fluorinated phenyl ethane compounds. The reaction raw materials are inexpensive, the preparation steps are simple, the preparation process is safe and mild, has good substrate compatibility, and the yield is high, thus improving the preparation efficiency.

[0012] Preferably, the molar ratio of the photocatalyst 4CzIPN, the reducing agent DIPEA, and the reaction substrate is (0.01-0.03):(18-24):(0.05-0.2).

[0013] Preferably, the molar ratio of the photocatalyst 4CzIPN, the reducing agent DIPEA, and the reaction substrate is 0.02:21.25:0.1.

[0014] Preferably, the water content in the solvent DCE is ≤30ppm.

[0015] Preferably, the molar amount of the reaction substrate to the volume of the solvent DCE is (0.05-0.2) mmol / (1-5) mL.

[0016] Preferably, the molar ratio of the reaction substrate to the volume of solvent DCE is 0.1 mmol / 3 mL.

[0017] Preferably, the wavelength of the blue light is 440-480nm.

[0018] Preferably, the wavelength of the blue light is 450nm.

[0019] Preferably, the purity of the sulfur hexafluoride gas is 90% or higher, and more preferably 99% or higher.

[0020] Preferably, the reaction temperature is 40-50℃.

[0021] Preferably, the reaction time is 18-24 hours.

[0022] The advantages of this invention are:

[0023] 1. This invention uses sulfur hexafluoride as a fluorinating agent and selects a certain ratio of raw materials and catalysts to efficiently prepare fluorinated phenyl ethane compounds. The reaction raw materials are inexpensive, the preparation process is safe and mild, and the substrate compatibility is good, thus improving the preparation efficiency.

[0024] 2. This invention is simple to operate, has a high yield, mild conditions, and low reagent prices. The amount of catalyst can be flexibly adjusted according to the type of substrate. There is no need to use low-temperature condensation. The pre-prepared photocatalyst-reducing agent solution is stable and suitable for a variety of substrates. The solvent is also easy to separate. Attached Figure Description

[0025] Figure 1 The hydrogen NMR spectrum of the product of Example 1 of this invention;

[0026] Figure 2 The image shows the hydrogen NMR spectrum of the product of Example 3 of this invention. Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0028] Example 1:

[0029] The reaction substrate is: (1-Phenylephethanol)

[0030] A method for preparing a fluorinated phenylethane compound includes the following steps:

[0031] Weigh out the photocatalyst 4CzIPN (0.002 mmol, 0.0016 g), and mix it with solvent DCE (3 mL, water ≤ 30 ppm), reducing agent DIPEA (1 mL, 2.125 mmol, 0.2746 g) and reaction substrate 1-phenylethanol (0.1 mmol, 0.0122 g). Place the mixture into a reaction vessel filled with sulfur hexafluoride gas (purity 99%) and react under 450 nm LED blue light irradiation at a reaction temperature of 40-50 °C for 20 h.

[0032] Reaction results: 1-Phenylenol was produced at 58%... 1 H-NMR yielded 1-fluorophenylethane

[0033] Example 2:

[0034] The difference between this embodiment and Example 1 is that: the reaction substrate is... (1-Phenylephethanol) (0.1 mmol, 0.0122 g) was replaced with 1-(4-methoxyphenyl)ethanol (0.1 mmol, 0.0152 g), other steps are the same as in Example 1.

[0035] Reaction results: 1-(4-methoxyphenyl)ethanol at 82% concentration 1 H-NMR yielded 1-fluoro(4-methoxyphenyl)ethane

[0036] Example 3

[0037] The difference between this embodiment and Example 1 is that: the reaction substrate is... (1-Phenylephethanol) (0.1 mmol, 0.0122 g) was replaced with 1-(4-cyanophenyl)ethanol (0.1 mmol, 0.0147 g), other steps are the same as in Example 1.

[0038] Reaction results: 1-(4-methoxyphenyl)ethanol at 26% 1 H-NMR yielded 1-fluoro(4-cyanophenyl)ethane

[0039] Example 4:

[0040] The difference between this embodiment and Example 2 is that the photocatalyst 4CzIPN, the reducing agent DIPEA, and the reaction substrate 1-(4-methoxyphenyl)ethanol are 0.01 mmol, 18 mmol, and 0.05 mmol, respectively, while the other steps are the same as in Example 2.

[0041] Example 5:

[0042] The difference between this embodiment and Example 2 is that the photocatalyst 4CzIPN, the reducing agent DIPEA, and the reaction substrate 1-(4-methoxyphenyl)ethanol are 0.03 mmol, 24 mmol, and 0.2 mmol, respectively, while the other steps are the same as in Example 2.

[0043] Example 6:

[0044] The difference between this embodiment and embodiment 2 is that the wavelength of the blue light is 440nm, while the other steps are the same as in embodiment 2.

[0045] Example 7:

[0046] The difference between this embodiment and embodiment 2 is that the wavelength of the blue light is 480nm, while the other steps are the same as in embodiment 2.

[0047] Example 8:

[0048] The difference between this embodiment and Embodiment 2 is that the purity of sulfur hexafluoride gas is 90%, while the other steps are the same as in Embodiment 2.

[0049] The yields of 1-fluoro(4-methoxyphenyl)ethane obtained in Examples 4-8 were slightly lower than those in Example 2.

[0050] Comparative Example 1:

[0051] Compared with the operation steps and effects of German patent DE10220901A1, this patent uses a strong reducing agent to activate sulfur hexafluoride gas.

[0052] (1) Procedure: Add tetrakis(dimethylamino)ethylene (5 mmol, 1.002 g), 1-phenylethanol (10 mmol, 1.2216 g), and N,N-dimethylformamide (3 mL) to a pressure-resistant glass reaction tube A, and cool it to -196°C in liquid nitrogen. Take a pressure-resistant glass reaction tube B and cool it to -196°C in liquid nitrogen, then pass sulfur hexafluoride gas through it, condensing it into a liquid state. Use a syringe to add liquid sulfur hexafluoride (5 mmol, 0.75 g) to tube A, seal it, and allow it to return to room temperature while stirring for 10 h.

[0053] (2) Effect: 1-Phenyleneethanol was given 1-fluoro-1-phenylethane in 20% yield.

[0054] Compared with Comparative Example 1, Examples 1-3 of the present invention are as follows:

[0055] As can be seen from the operation steps and effects, the present invention is simple to operate, has a high yield, mild conditions, low reagent price, and the amount of catalyst can be flexibly adjusted according to the type of substrate. It does not require low temperature condensation, the pre-prepared photocatalyst-reducing agent solution is stable and suitable for a variety of substrates, and the solvent dichloroethane is easy to separate.

[0056] Comparative Example 1 uses a high-cost strong reducing agent, tetra(dimethylamino)ethylene (approximately 700 yuan / g), which requires the use of liquid nitrogen. After the test tube returns to room temperature, the internal pressure increases, posing a risk of explosion. Furthermore, the use of the solvent N,N-dimethylformamide is not conducive to the separation and purification of the product.

[0057] The yield of most embodiments of the present invention is higher than that of Comparative Example 1, and the yield of the present invention can reach up to 82%.

[0058] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a fluorinated phenylethane compound, characterized in that, Includes the following steps: The photocatalyst 4CzIPN, solvent DCE, reducing agent DIPEA, and reaction substrate were mixed and reacted under blue light irradiation in a sulfur hexafluoride gas atmosphere. The reaction substrate has the following structural formula: The compound wherein R is H, alkoxy or cyano; the molar ratio of the photocatalyst 4CzIPN, the reducing agent DIPEA to the reaction substrate is (0.01-0.03):(18-24):(0.05-0.2).

2. The preparation method according to claim 1, characterized in that, The molar ratio of the photocatalyst 4CzIPN, the reducing agent DIPEA, and the reaction substrate is 0.01:18:0.

05.

3. The preparation method according to claim 1, characterized in that, The molar ratio of the photocatalyst 4CzIPN, the reducing agent DIPEA, and the reaction substrate is 0.02:21.25:0.

1.

4. The preparation method according to claim 1, characterized in that, The water content in the solvent DCE is ≤30ppm.

5. The preparation method according to claim 1, characterized in that, The ratio of the molar amount of the reaction substrate to the volume of the solvent DCE is (0.05-0.2) mmol / (1-5) mL.

6. The preparation method according to claim 5, characterized in that, The molar ratio of the reaction substrate to the volume of solvent DCE is 0.1 mmol / 3 mL.

7. The preparation method according to claim 1, characterized in that, The wavelength of the blue light is 440-480nm.

8. The preparation method according to claim 7, characterized in that, The wavelength of the blue light is 450nm.

9. The preparation method according to claim 1, characterized in that, The purity of the sulfur hexafluoride gas is above 90%.

10. The preparation method according to claim 1, characterized in that, The reaction time is 18-24 hours.

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