A method for preparing fluorine-containing diphenylmethane compounds using sulfur hexafluoride as a fluorinating reagent

Abstract

The application discloses a method for preparing fluorine-containing diphenylmethane compounds by using sulfur hexafluoride as a fluorination reagent, and belongs to the technical field of organic chemical synthesis. The preparation method comprises the following steps: (1) mixing a photocatalyst, a solvent and a reducing agent, and performing ultrasonic treatment to obtain solution A; mixing a reaction substrate and the solvent to obtain solution B; the photocatalyst is one or more of 4CzIPN, Ir[dF(CF3)ppy]2(dtbpy))PF6, 9-thioxanthone and 10-phenylphenothiazine; the reaction substrate is a compound with a structural formula of R1 and R2 are both H, alkoxy or halogen; (2) mixing the obtained solution A and solution B in a sulfur hexafluoride gas atmosphere, and performing reaction under blue light illumination, and the fluorine-containing diphenylmethane compounds are obtained. The method has the beneficial effects that the fluorine-containing diphenylmethane compounds are efficiently prepared by using sulfur hexafluoride as the fluorination reagent, and by selecting raw materials and catalysts with certain proportions; the reaction raw materials are cheap; the preparation process is safe, mild, has good substrate compatibility and high preparation efficiency.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and specifically to a method for preparing fluorinated diphenylmethane compounds using sulfur hexafluoride as a fluorinating agent. 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 to address the issues of excessively high reagent activity, harsh reaction conditions, dangerous operation, and high cost in existing dehydroxylation and fluorination conversion methods for diphenylmethanol 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 diphenylmethane compounds, comprising the following steps:

[0009] (1) A certain amount of photocatalyst, solvent, and reducing agent are mixed and ultrasonically treated to obtain solution A; the reaction substrate is mixed with the solvent to obtain solution B; the photocatalyst is one or more of 4CzIPN, Ir[dF(CF3)ppy]2(dtbpy))PF6, 9-thioxanone, and 10-phenylphenthiazide; the reaction substrate has the following structural formula: The compound in which R1 and R2 are both H, alkoxy or halogen;

[0010] (2) In a sulfur hexafluoride gas atmosphere, mix solution A and solution B obtained in step (1) and react under blue light irradiation to obtain the solution.

[0011] Beneficial effects: This invention uses sulfur hexafluoride as the fluorinating agent and selects a certain ratio of raw materials and catalysts to efficiently prepare fluorinated diphenylmethane 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.

[0012] Note: The Chinese name of 4CzIPN is 2,4,5,6-tetra(9-carbazolyl)-isophenyladionitrile; the Chinese name of Ir[dF(CF3)ppy]2(dtbpy))PF6 is 4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridineN1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridylN]phenyl-C]iridium hexafluorophosphate(III).

[0013] Preferably, the reducing agent in step (1) is one or more of N,N-diisopropylethylamine, triethylamine, N,N,N',N'-tetramethylethylenediamine, and diisopropylphenylamine.

[0014] Preferably, the solvent in step (1) is one or more of 1,2-dichloroethane, dichloromethane, ethyl acetate, and acetonitrile.

[0015] Preferably, in step (1), the molar ratio of photocatalyst, reducing agent and reaction substrate is (0.005-0.02):(15-25):(0.05-0.2).

[0016] Preferably, in step (1), the molar ratio of photocatalyst, reducing agent and reaction substrate is 0.01:21.25:0.1.

[0017] Preferably, the ultrasonic treatment time in step (1) is 5-15 seconds.

[0018] Preferably, the wavelength of the blue light in step (2) is 440-480nm.

[0019] Preferably, the wavelength of the blue light in step (2) is 450 nm.

[0020] Preferably, the purity of sulfur hexafluoride gas in step (2) is above 99%.

[0021] Preferably, the reaction solution is magnetically stirred during the reaction process in step (2).

[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 diphenylmethane 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 hydrogen NMR spectrum of the product of Example 11 of this invention;

[0027] Figure 3 The image shows the hydrogen NMR spectrum of the product of Example 12 of this invention. Detailed Implementation

[0028] 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.

[0029] Example 1:

[0030] The reaction substrate is: (benzyl alcohol)

[0031] A method for preparing a fluorinated diphenylmethane compound includes the following steps:

[0032] (1) Weigh the photocatalyst 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN, 0.01 equiv, 0.0008 g), add the solvent 1,2-dichloroethane (DCE) (2 mL, water ≤ 30 ppm) to a 10 mL cylindrical glass bottle A, then use a 1 mL syringe to add the reducing agent N,N-diisopropylethylamine (DIPEA, 2.125 mmol, 0.2746 g) to the bottle, shake for 5-10 s, and sonicate for 10 s to completely dissolve the components to prepare solution A, which is then drawn into a 5 mL syringe for later use; weigh the reaction substrate diphenylmethanol (0.1 mmol, 0.0184 g), add the solvent DCE (1 mL, water ≤ 30 ppm) to a 10 mL cylindrical glass bottle B, shake for 5-10 s to prepare solution B, which is then drawn into a 2.5 mL syringe for later use.

[0033] (2) Place an A615 type PTFE magnetic stir bar in a 10mL Schlenk tube, and screw on the PTFE stopcock to seal the tube opening, connecting the tube cavity to the branch pipe opening. Take a stoppered high-vacuum three-way gas valve, and connect its interfaces to the Schlenk tube, the vacuum pump, and sulfur hexafluoride gas respectively. Connect the Schlenk tube to the vacuum pump and evacuate the air in the tube (for more than 10 seconds); connect the sulfur hexafluoride gas to the Schlenk tube and introduce sulfur hexafluoride gas (for more than 3 seconds). One set of evacuation and venting constitutes one gas exchange cycle. Repeat the gas exchange at least 5 times, and then stay in the venting state to make the tube have a positive pressure of pure sulfur hexafluoride gas (purity of 99% or higher).

[0034] Open the stopcock of the Schlenk tube and quickly inject solutions A and B into the sulfur hexafluoride gas atmosphere. Close the stopcock to completely seal the Schlenk tube cavity and disconnect it from the vacuum pump and sulfur hexafluoride gas. Place the sealed Schlenk tube into the parallel light reactor and set the conditions to 450nm LED blue light source, 18W power, 200rpm magnetic stirring speed, and react for 20h.

[0035] Reaction results: benzyl alcohol was produced at 89%... 1 H-NMR yielded 1-fluoro-1,1-diphenylmethane

[0036]

[0037] Example 2:

[0038] The difference between this embodiment and Embodiment 1 is that the solvent 1,2-dichloroethane (DCE) in step (1) is replaced with dichloromethane (DCM), while the other steps are the same as in Embodiment 1.

[0039] Reaction results: diphenylethanol at 18% 1 1-Fluoro-1,1-diphenylmethane was obtained by H-NMR yield.

[0040] Example 3:

[0041] The difference between this embodiment and Example 1 is that the solvent 1,2-dichloroethane (DCE) in step (1) is replaced with ethyl acetate (EA), while the other steps are the same as in Example 1.

[0042] Reaction results: diphenylethanol was produced at 26%... 1 1-Fluoro-1,1-diphenylmethane was obtained by H-NMR yield.

[0043] Example 4:

[0044] The difference between this embodiment and Embodiment 1 is that the solvent 1,2-dichloroethane (DCE) in step (1) is replaced with acetonitrile (MeCN), while the other steps are the same as in Embodiment 1.

[0045] Reaction results: benzyl alcohol was produced at 19%... 1 1-Fluoro-1,1-diphenylmethane was obtained by H-NMR yield.

[0046] Example 5:

[0047] The difference between this embodiment and Example 1 is that the photocatalyst 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN, 0.01equiv, 0.0008g) in step (1) is replaced with Ir[dF(CF3)ppy]2(dtbpy))PF6 (0.01equiv, 0.0011g), and the other steps are the same as in Example 1.

[0048] Reaction results: diphenylethanol at 22% 1 1-Fluoro-1,1-diphenylmethane was obtained by H-NMR yield.

[0049] Example 6:

[0050] The difference between this embodiment and Example 1 is that the photocatalyst 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN, 0.01 equiv, 0.0008 g) in step (1) is replaced with 9-thioxanthen-9-one (0.01 equiv, 0.0002 g), and the other steps are the same as in Example 1.

[0051] Reaction results: diphenylethanol at 7% 1 1-Fluoro-1,1-diphenylmethane was obtained by H-NMR yield.

[0052] Example 7:

[0053] The difference between this embodiment and Example 1 is that the photocatalyst 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN, 0.01equiv, 0.0008g) in step (1) is replaced with 10-phenylphenthiazine (N-Ph-PTZ) (0.01equiv, 0.0003g), and the other steps are the same as in Example 1.

[0054] Reaction results: diphenylethanol was produced at 16%... 1 1-Fluoro-1,1-diphenylmethane was obtained by H-NMR yield.

[0055] Example 8:

[0056] The difference between this embodiment and Embodiment 1 is that the reducing agent N,N-diisopropylethylamine (DIPEA, 21.25 equiv, 0.2746 g) in step (1) is replaced with triethylamine (TEA) (21.25 equiv, 0.2150 g), and the other steps are the same as in Embodiment 1.

[0057] Reaction results: diphenylethanol was produced at 51%... 1 1-Fluoro-1,1-diphenylmethane was obtained by H-NMR yield.

[0058] Example 9:

[0059] The difference between this embodiment and Example 1 is that the reducing agent N,N-diisopropylethylamine (DIPEA, 21.25 equiv, 0.2746 g) in step (1) is replaced with N,N,N',N'-tetramethylethylenediamine (TMEDA) (21.25 equiv, 0.2469 g), and the other steps are the same as in Example 1.

[0060] Reaction results: benzyl alcohol was produced at 34%... 1 1-Fluoro-1,1-diphenylmethane was obtained by H-NMR yield.

[0061] Example 10:

[0062] The difference between this embodiment and Embodiment 1 is that the reducing agent N,N-diisopropylethylamine (DIPEA, 21.25 equiv, 0.2746 g) in step (1) is replaced with diisopropylphenylamine (DIPBA) (21.25 equiv, 0.4065 g), and the other steps are the same as in Embodiment 1.

[0063] Reaction results: benzyl alcohol was produced at 54%...1 1-Fluoro-1,1-diphenylmethane was obtained by H-NMR yield.

[0064] Example 11:

[0065] The difference between this embodiment and Example 1 is that the reaction substrate in step (1) is... (benzyl alcohol) (0.1 mmol, 0.0184 g) replaced with (4,4'-Dimethoxydiphenylethanol) (0.1 mmol, 0.0244 g), other steps are the same as in Example 1.

[0066] Reaction results: 4,4'-dimethoxydiphenylethanol produced 95% 1 H-NMR yielded 4,4'-dimethoxydiphenylfluoromethane

[0067] Example 12:

[0068] The difference between this embodiment and Example 1 is that the reaction substrate in step (1) is... (benzyl alcohol) (0.1 mmol, 0.0184 g) replaced with (4,4'-Difluorodiphenylethanol) (0.1 mmol, 0.0220 g), other steps are the same as in Example 1.

[0069] Reaction results: 4,4'-difluorodiphenylmethanol achieved 83% [result]. 1 H-NMR yielded 4,4'-difluorodiphenylmethylfluoromethane.

[0070] Example 13:

[0071] The difference between this embodiment and Example 1 is that the reaction substrate in step (1) is... (benzyl alcohol) (0.1 mmol, 0.0184 g) replaced with (4-Fluoro-4'-methoxydiphenylethanol) (0.1 mmol, 0.0232 g), other steps are the same as in Example 1.

[0072] Reaction results: 4-fluoro-4'-methoxydiphenylethanol was produced at 85%... 1 H-NMR yielded 4-fluoro-4'-methoxydiphenylfluoromethane.

[0073] Example 14:

[0074] The difference between this embodiment and Example 1 is that the photocatalyst 4CzIPN, the reducing agent DIPEA, and the reaction substrate diphenylmethanol are 0.005 mmol, 15 mmol, and 0.05 mmol, respectively, while the other steps are the same as in Example 1.

[0075] Example 15:

[0076] The difference between this embodiment and Example 1 is that the photocatalyst 4CzIPN, the reducing agent DIPEA, and the reaction substrate diphenylmethanol are 0.02 mmol, 25 mmol, and 0.2 mmol, respectively, while the other steps are the same as in Example 1.

[0077] Example 16:

[0078] The difference between this embodiment and Embodiment 1 is that the wavelength of the blue light is 440nm, while the other steps are the same as in Embodiment 1.

[0079] Example 17:

[0080] The difference between this embodiment and Embodiment 1 is that the wavelength of the blue light is 480nm, while the other steps are the same as in Embodiment 1.

[0081] The yields of 1-fluoro-1,1-diphenylmethane obtained in Examples 14-17 were all slightly lower than those in Example 1.

[0082] Comparative Example 1:

[0083] Compared with the operation steps and effects of German patent DE10220901A1, this patent uses a strong reducing agent to activate sulfur hexafluoride gas.

[0084] (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.

[0085] (2) Effect: 1-Phenyleneethanol was given 1-fluoro-1-phenylethane in 20% yield.

[0086] Compared with Comparative Example 1, Examples 1-13 of the present invention are as follows:

[0087] 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.

[0088] 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.

[0089] 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 95%.

[0090] 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 producing a fluoro-diphenylmethane compound, characterized by, Includes the following steps: (1) Preparation of reaction raw materials: A certain amount of photocatalyst, solvent and reducing agent are mixed and ultrasonically treated to obtain solution A; the reaction substrate is mixed with solvent to obtain solution B; the photocatalyst is 4CzIPN; the reaction substrate has the following structural formula: The compound, wherein R1 and R2 are both H, alkoxy, or halogen; the molar ratio of the photocatalyst, reducing agent, and reaction substrate is (0.005-0.02):(15-25):(0.05-0.2); the reducing agent is one or more of N,N-diisopropylethylamine, triethylamine, N,N,N',N'-tetramethylethylenediamine, and diisopropylphenylamine; the solvent is 1,2-dichloroethane. (2) In a sulfur hexafluoride gas atmosphere, mix solution A and solution B obtained in step (1) and react them under blue light to obtain the solution.

2. The production method according to claim 1, characterized by, The reducing agent in step (1) is N,N-diisopropylethylamine.

3. The preparation method according to claim 1, characterized in that, The reducing agent in step (1) is triethylamine.

4. The production method according to claim 1, characterized by, In step (1), the molar ratio of photocatalyst, reducing agent and reaction substrate is 0.02:25:0.

2.

5. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of photocatalyst, reducing agent and reaction substrate is 0.01:21.25:0.

1.

6. The method of claim 1, wherein, The ultrasonic treatment time in step (1) is 5-15 s.

7. The preparation method according to claim 1, characterized in that, The wavelength of blue light in step (2) is 440-480nm.

8. The method of claim 1, wherein, The wavelength of the blue light in step (2) is 450nm.

9. The method of claim 1, wherein, The purity of sulfur hexafluoride gas in step (2) is above 99%.

10. The method of claim 1, wherein, In step (2), the reaction solution is magnetically stirred during the reaction process.

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