3, 3-difluoropropenyl thioether compound and preparation method thereof

Abstract

The invention discloses a method for preparing a 3, 3-difluoropropenyl thioether compound through photocatalysis, and belongs to the technical field of organic synthesis. The method comprises the following steps: under the protection of inert gas, by taking 3, 3-difluoroallyl sulfide and electron-deficient olefin as raw materials, adding a photocatalyst, triethylene diamine, sodium dihydrogen phosphate and a solvent, carrying out photocatalytic reaction under the conditions that the wavelength is 450-460 nm, the temperature is 25-35 DEG C and the illumination of a 40W LED light source, and carrying out column chromatography purification to obtain a target product. According to the method, a visible light catalysis strategy is adopted, and the compound containing the alpha, alpha-difluoroallyl fragment is efficiently constructed. Compared with a traditional method, the method has the advantages of mild reaction conditions, no need of a transition metal catalyst, good functional group compatibility, high atom economy and the like. The synthesized 3, 3-difluoropropenyl thioether compound has important application value in the fields of drug molecule design, functional material development, pesticide synthesis and the like. The invention provides a new way for green synthesis of fluorine-containing organic compounds.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for preparing 3,3-difluoropropenyl sulfide compounds. Background Art

[0002] The α,α-difluoroallyl fragment (-F 2 C-C=C-) is widely used in medicine, pesticides, and materials science due to its unique chemical structure. For example, the drugs tafluprost for reducing intraocular pressure and grazoprevir for anti-hepatitis virus both contain this structural unit. In addition, α,α-difluoroallyl can participate in various chemical reactions, such as nucleophilic substitution, cycloaddition reactions (Chin.Chem.Lett. 2025, 36, 110213), etc., to construct multi-functionalized organic molecules, providing an important method for synthesizing the skeletal structures of natural products, drug intermediates, etc.

[0003] Currently, the main methods for directly introducing the α,α-difluoroallyl fragment are as follows: 1) Palladium-catalyzed coupling reactions based on 3-bromo-3,3-difluoropropene (BDFP) (J.Am.Chem.Soc. 2014, 136, 1230; Nat.Commun. 2021, 12, 6551); 2) Palladium-catalyzed coupling reactions based on 3,3-difluoroallyl quaternary ammonium salts (Chem.Sci. 2019, 10, 8701) and S N 2’ (Nat.Commun. 2021, 12, 3257) reactions; 3) Palladium-catalyzed coupling reactions based on 3,3-difluoroallyl boronic esters (Angew.Chem.Int.Ed. 2021, 60, 25746); 4) Copper-catalyzed coupling reactions based on 3,3-difluoroallyl sulfonium salts (Angew.Chem.Int.Ed. 2022, 61, e202210103) and S N 2’ (Chem.Sci. 2024, 15, 2937) reactions, etc. However, all of the above strategies have some deficiencies, such as poor atom economy, the need for transition metal catalysts, limited reaction types, etc. Therefore, it is still of great value to develop a new difluoroallylation method to achieve the rapid and efficient construction of this potentially bioactive skeletal structure. Summary of the Invention

[0004] The present invention provides a new method for preparing 3,3-difluoropropenyl sulfide compounds through visible light catalysis. This method can rapidly introduce the α,α-difluoroallyl fragment and has the advantages of simple operation, economic and environmental protection, good atom economy, mild conditions, and good functional group compatibility.

[0005] To solve the technical problems of the present invention, the technical solution proposed is: a new method for preparing 3,3-difluoropropenyl sulfide compounds by photocatalysis, comprising the following steps:

[0006] Step 1: Under an inert gas atmosphere, 3,3-difluoroallyl aryl sulfide (1), electron-deficient olefin (2), triethylenediamine, [Acr-Mes 2 - t Bu] + [BF 4 - (photocatalyst) and a solvent are successively added to a reaction tube and magnetically stirred evenly to obtain a mixture;

[0007] Step 2: Under an inert gas atmosphere, the above mixture is magnetically stirred under the irradiation of an LED lamp (wavelength 450 - 460 nm, power 40 W) and at room temperature until the reaction is complete, and the 3,3-difluoropropenyl sulfide compound (3) is separated from the reaction mixture by flash column chromatography.

[0008] The specific reaction route is as follows:

[0009]

[0010] Among them, R 1 is 4-methylphenyl, adamantyl; R 2 is 4-cyanophenyl, 4-methoxycarbonylphenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluoro-3-methoxyphenyl, naphthalen-1-yl, 3,5-dimethoxyphenyl, 4-acetylphenyl, hydrogen; R 3 is methoxycarbonyl, benzyloxycarbonyl, benzoyl; R 4 is phenyl, hydroxymethyl, hydrogen.

[0011] Preferably, in Step 1 and Step 2, the inert gas is any one of nitrogen and argon.

[0012] Preferably, in Step 1, the solvent is dichloromethane.

[0013] Preferably, in Step 1, the photocatalyst is [Acr-Mes 2 - t Bu] + [BF 4 - .

[0014] Preferably, in Step 1, the 3,3-difluoroallyl sulfide, electron-deficient olefin, triethylenediamine, sodium dihydrogen phosphate, [Acr-Mes 2 - t Bu] + [BF 4- The molar ratio of [] is 1:2:0.2:0.2:0.01 to 0.03.

[0015] Preferably, in the second step, the wavelength of the LED light source is 450 - 460 nm, the power is 40 W, and the reaction temperature is 25 - 35 °C.

[0016] Preferably, in the second step, the separation conditions of the flash column chromatography are as follows: passing the reaction product through a chromatography column filled with 200 - 300 mesh silica gel, and using a mixed solvent of ethyl acetate and petroleum ether as the eluent for column chromatography separation to obtain a pure 3,3 - difluoropropenyl sulfide compound.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0018] 1. The present invention provides a 3,3 - difluoropropenyl sulfide and its synthesis method, with mild reaction conditions, high reaction efficiency, and easy separation of products.

[0019] 2. By optimizing the reaction conditions, the present invention can obtain the target compound with a high yield, with the highest yield reaching 74%, good reaction universality, and relatively high atom economy.

[0020] 3. 3,3 - Difluoropropenyl sulfide can be further subjected to desulfurization derivatization to construct compounds containing α,α - difluoroallyl fragments with more diverse substituent types. Description of the Drawings

[0021] Figure 1 is the nuclear magnetic resonance 1 1H spectrum of compound 3a;

[0022] Figure 2 is the nuclear magnetic resonance 13 13C spectrum of compound 3a;

[0023] Figure 3 is the nuclear magnetic resonance 1 1H spectrum of compound 3b;

[0024] Figure 4 is the nuclear magnetic resonance 13 13C spectrum of compound 3b;

[0025] Figure 5 is the nuclear magnetic resonance 1 1H spectrum of compound 3c;

[0026] Figure 6 is the nuclear magnetic resonance 13 13C spectrum of compound 3c;

[0027] Figure 7 is the nuclear magnetic resonance 1 1H spectrum of compound 3d;

[0028] Figure 8 is the nuclear magnetic resonance of compound 3d 13 C spectrum; Detailed implementation mode

[0029] In order to make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0030] The method of the present invention uses compounds with different structures as reaction substrates. Through the same reaction process, various types of 3,3-difluoropropenyl sulfide compounds can be synthesized. The specific structural formula of the target product is as follows:

[0031] Example 1

[0032]

[0033] (1) Under a nitrogen atmosphere, 2-(4-cyanophenyl)-3,3-difluoroallyl (4-methylphenyl) sulfide 1a (60.2 mg, 0.2 mmol, 1.0 equiv), methyl 2-phenylacrylate 2a (64.8 mg, 0.4 mmol, 2.0 equiv), [Acr-Mes 2 - t Bu] + [BF 4 - (1.2 mg, 0.002 mmol, 0.01 equiv), triethylenediamine (4.8 mg, 0.04 mmol, 0.2 equiv), sodium dihydrogen phosphate (4.48 mg, 0.04 mmol, 0.2 equiv) and the solvent dichloromethane (1 mL) were successively added to the reaction tube and stirred magnetically until homogeneous to obtain a mixture;

[0034] (2) The above mixture was magnetically stirred under irradiation with a 40W LED light source at a wavelength of 450 - 460 nm and at 25 - 35 °C until the reaction was complete. Compound 3a (65.7 mg, 0.142 mmol) was separated from the reaction mixture by flash column chromatography as a colorless oil, and the separation yield was 71%.

[0035] The characterization results of compound 3a are as follows, 1 H NMR (400 MHz, CDCl 3) δ 7.72 - 7.65 (m, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.33 - 7.26 (m, 5H), 7.23 (dd, J = 7.9, 1.8 Hz, 2H), 7.19 - 7.13 (m, 2H), 7.08 (t, J = 2.0 Hz, 1H), 3.93 (dd, J = 9.2, 4.0 Hz, 1H), 3.65 (s, 3H), 3.01 - 2.89 (m, 1H), 2.35 (s, 3H), 2.24 - 2.11 (m, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ -90.19 (dd, J = 21.7, 10.7 Hz), -90.38 (dd, J = 22.2, 14.1 Hz), -93.29 (ddd, J = 246.4, 21.5, 9.7 Hz, for minor isomer), -94.52 (ddd, J = 246.3, 22.0, 12.6 Hz, for minor isomer), -95.95 (dd, J = 20.8, 10.9 Hz), -96.18 (dd, J = 21.8, 13.5 Hz). 13 C NMR (100 MHz, CDCl 3 ):δ 173.40, 139.01, 138.63, 138.09, 135.03 (t, J = 9.5 Hz), 132.52, 131.30, 130.54, 130.33, 129.02, 127.81 (d, J = 7.1 Hz), 121.98 (d, J = 245.0 Hz), 118.61, 112.47, 52.56, 45.31 (t, J = 3.3 Hz), 40.37 (t, J = 26.5 Hz), 21.21.

[0036] Example 2

[0037]

[0038] Under a nitrogen atmosphere, 2-(4-methoxycarbonylphenyl)-3,3-difluoroallyl (4-methylphenyl) sulfide 1b (66.8 mg, 0.2 mmol, 1.0 equiv), methyl 2-phenylacrylate (64.8 mg, 0.4 mmol, 2.0 equiv), [Acr-Mes2- t Bu] + [BF 4 -(Photocatalyst) (1.2 mg, 0.002 mmol, 0.01 equiv), triethylenediamine (4.8 mg, 0.04 mmol, 0.2 equiv), sodium dihydrogen phosphate (4.48 mg, 0.04 mmol, 0.2 equiv), and the solvent dichloromethane (1 mL) were successively added to a reaction tube and stirred magnetically until homogeneous to obtain a mixture; the above mixture was magnetically stirred under irradiation with a 40 W LED light source at a wavelength of 450 - 460 nm and at 25 - 35 °C until the reaction was complete, and compound 3b (73.5 mg, 0.148 mmol) was separated from the reaction mixture by flash column chromatography as a colorless oil, with a separation yield of 74%.

[0039] The characterization results of compound 3b are as follows. 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 - 8.00 (m, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.34 - 7.28 (m, 3H), 7.28 - 7.25 (m, 2H), 7.25 - 7.20 (m, 2H), 7.15 (d, J = 7.7 Hz, 2H), 7.06 (t, J = 1.9 Hz, 1H), 3.93 (dd, J = 9.4, 4.2 Hz, 1H), 3.92 (s, 3H), 3.64 (s, 3H), 3.00 - 2.86 (m, 1H), 2.24 - 2.10 (m, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ -93.61 (ddd, J = 244.6, 21.2, 9.0 Hz, for minor isomer), -95.03 (ddd, J = 244.6, 22.4, 12.7 Hz, for minor isomer), -96.25 (dd, J = 22.0, 9.4 Hz), -96.69 (dd, J = 22.5, 12.3 Hz). 13 C NMR (100 MHz, CDCl 3 ) : δ 173.48, 166.79, 139.00, 138.35, 138.22, 134.06 (t, J = 9.8 Hz), 131.22, 130.62, 130.25, 130.03, 129.75, 128.99, 127.79 (d, J = 2.8 Hz), 120.96 (t, J = 245.2 Hz), 52.54, 52.34, 40.38 (t, J = 26.5 Hz), 21.22.

[0040] Example 3

[0041]

[0042] Under a nitrogen atmosphere, 3,3-difluoroallyl (4-methylphenyl) sulfide 1c (40 mg, 0.2 mmol, 1.0 equiv), methyl 2-phenylacrylate (64.8 mg, 0.4 mmol, 2.0 equiv), [Acr-Mes2- t Bu] + [BF 4 - (photocatalyst) (3.6 mg, 0.002 mmol, 0.03 equiv), triethylenediamine (4.8 mg, 0.04 mmol, 0.2 equiv), sodium dihydrogen phosphate (4.48 mg, 0.04 mmol, 0.2 equiv), and the solvent dichloromethane (1 mL) were successively added to a reaction tube and stirred magnetically until homogeneous to obtain a mixture; the above mixture was magnetically stirred under irradiation with a 40 W LED light source at a wavelength of 450 - 460 nm and at 25 - 35 °C until the reaction was complete, and the pure target compound 3c (49.2 mg, 0.136 mmol) was separated from the reaction mixture by flash column chromatography as a colorless oil, with a separation yield of 68%.

[0043] The characterization results of compound 3c are as follows. 1 H NMR (400 MHz, CDCl3) δ 7.35 - 7.29 (m, 4H), 7.29 - 7.26 (m, 3H), 7.19 (d, J = 7.9 Hz, 2H), 6.80 (dt, J = 15.3, 2.4 Hz, 1H), 5.39 - 5.29 (m, 1H), 3.85 (dd, J = 9.6, 3.9 Hz, 1H), 3.67 (s, 3H), 3.00 - 2.86 (m, 1H), 2.37 (s, 3H), 2.79 - 2.15 (m, 1H). 19 F NMR (376 MHz, CDCl3) δ -94.13 (dddd, J = 243.1, 20.7, 10.9, 10.9 Hz), -96.67 (dddd, J = 243.3, 19.5, 12.6, 12.6 Hz). 13 C NMR (101 MHz, CDCl3) δ 173.62, 139.05, 138.28, 133.75 (t, J = 9.9 Hz), 132.98, 130.46, 129.02, 127.74 (d, J = 10.3 Hz), 120.47 (t, J = 240.6 Hz), 120.10 (t, J = 26.5 Hz), 52.63, 45.50, 41.29 (t, J = 27.3 Hz), 21.35.

[0044] Example 4

[0045]

[0046] Under a nitrogen atmosphere, 3,3-difluoroallyl (4-methylphenyl) sulfide 1c (40 mg, 0.2 mmol, 1.0 equiv), benzyl acrylate 2b (64.8 mg, 0.4 mmol, 2.0 equiv), [Acr-Mes2- t Bu] + [BF 4 - (photocatalyst) (3.6 mg, 0.002 mmol, 0.03 equiv), triethylenediamine (4.8 mg, 0.04 mmol, 0.2 equiv), sodium dihydrogen phosphate (4.48 mg, 0.04 mmol, 0.2 equiv), and the solvent dichloromethane (1 mL) were successively added to a reaction tube and stirred magnetically until homogeneous to obtain a mixture; the above mixture was magnetically stirred under irradiation with a 40 W LED light source at a wavelength of 450 - 460 nm and at 25 - 35 °C until the reaction was complete, and the pure target compound 3d (33.4 mg, 0.092 mmol) was separated from the reaction mixture by flash column chromatography, with a separation yield of 46%.

[0047] The characterization results of compound 3d are as follows, where 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (td, J = 8.2, 7.2, 5.1 Hz, 7H), 7.21 - 7.15 (m, 2H), 6.82 (dt, J = 15.3, 2.4 Hz, 1H), 5.41 (dt, J = 15.3, 11.1 Hz, 1H), 5.13 (s, 2H), 2.53 (dd, J = 8.7, 6.8 Hz, 2H), 2.37 (s, 3H), 2.32 - 2.19 (m, 2H). 19 F NMR (376 MHz, CDCl 3 ) δ -96.01 (q, J = 14.8, 14.0 Hz). 13 C NMR (101 MHz, CDCl 3 ) δ 172.18, 139.07, 135.72, 133.94, 132.98, 131.31, 130.49, 129.96, 128.75, 128.48 (d, J = 7.0 Hz), 127.73, 120.69 (t, J = 239.5 Hz), 120.13 (t, J = 26.7 Hz), 66.81, 32.89 (t, J = 28.6 Hz), 27.65, 21.36.

[0048] Examples 5 to 12

[0049] Examples 5 to 12 are basically the same as Example 1, except that the substituents in 3,3-difluoroallyl sulfide and the electron-deficient olefin compound are different. The specific structures of the 3,3-difluoropropenyl sulfide compounds are shown in the following table:

[0050] Table 1 Examples 5 to 10

[0051]

[0052]

[0053] The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A 3,3-difluoropropylene sulfide compound, characterized in that: The chemical structure of the compound is as follows: Among them, R 1 4-methylphenyl, 4-chlorophenyl, adamantyl; R 2 is 4-cyanophenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluoro-3-methoxyphenyl, naphth-1-yl, 4-methoxycarbonylphenyl, 3,5-dimethoxyphenyl, 4-acetylphenyl; R 3 is methoxycarbonyl, benzyloxycarbonyl, benzoyl; R 4 It is phenyl, hydroxymethyl, and hydrogen.

2. The method for preparing 3,3-difluoropropylene sulfide compounds by photocatalysis according to claim 1, characterized in that: The following steps are involved: Step 1: Under an inert gas atmosphere, 3,3-difluoroallyl sulfide, electron-deficient olefin, triethylenediamine, [Acr-Mes2- t Bu] + [BF4 - ](photocatalyst) and solvent are sequentially added into the reaction tube and magnetically stirred to obtain a mixture; Step 2: In an inert gas atmosphere, the mixture is irradiated with an LED lamp (wavelength 450-460 nm, power 40 W) and magnetically stirred at room temperature until the reaction is complete, and 3,3-difluoropropenyl sulfide compounds are separated from the reaction mixture by rapid column chromatography.

3. The method for preparing 3,3-difluoropropylene sulfide compounds according to claim 1, characterized in that: In step 1 and step 2, the inert gas is any one of nitrogen and argon.

4. The method for preparing 3,3-difluoropropenyl sulfide compounds according to claim 1, characterized in that: The photocatalyst is [Acr-Mes2- t Bu] + [BF4 - ], [Acr-Mes2-Ph] + [BF4 - ] is one of the following.

5. The method for preparing 3,3-difluoropropenyl sulfide compounds according to claim 1, characterized in that: The solvent is one of dichloromethane, N,N-dimethylformamide and 1,2-dichloroethane.

6. The method for preparing 3,3-difluoropropenyl sulfide compounds according to claim 1, characterized in that: The reaction temperature is 25-35°C; the reaction time is 24-48h.

7. The method for preparing 3,3-difluoropropenyl sulfide compounds according to claim 1, characterized in that: The molar ratio of 3,3-difluoroallyl sulfide, electron-deficient olefin, triethylenediamine, sodium dihydrogen phosphate and photocatalyst is 1:2:0.2:0.2:0.01-0.03.

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