Method for preparing electron-deficient 1, 3-substituted benzene ring fluorine-containing compound through photo-cobalt concerted catalysis

Abstract

The invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for preparing an electron-deficient 1, 3-substituted benzene ring fluorine-containing compound through photo-cobalt concerted catalysis. Under the action of a composite catalyst, enamine and fluorine-containing aryl butadiene are promoted to react, and the composite catalyst is formed by mixing a visible light catalyst and a metal catalyst. The photocatalyst has the advantages that the reaction process is safe and controllable, and the preparation and production operation is simplified; a Kessil lamp is used as a reaction light source, is safe and environment-friendly, has high energy utilization efficiency, and can efficiently realize conversion from light energy to chemical energy; the used raw materials are low in price and easy to obtain, and the preparation process is simple. The process is mild in condition and good in regioselectivity, a series of electron-deficient group substituted [1, 3]-benzene ring fluorine-containing compounds can be efficiently obtained only through one-step reaction, and designability and application prospects of the compounds are greatly expanded.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a method for preparing electron-deficient 1,3-substituted benzene ring fluorinated compounds by photocobalt synergistic catalysis. Background Technology

[0002] Benzene rings are a basic aromatic ring structure widely found in many organic compounds, such as pharmaceuticals, dyes, and pesticides. Among these, fluorinated compounds with 1,3-substituted benzene rings are of great significance in drug design, serving as bioisosteres (such as nortricyclanes) to replace traditional benzene rings and improve drug solubility and stability. However, compared to 1,2-disubstituted, 1,4-disubstituted, or 1,2,4-trisubstituted benzene rings, the synthesis and applications of 1,3-disubstituted and 1,3,5-trisubstituted benzene rings are relatively limited, and their synthetic methods have consistently faced numerous challenges. Traditionally, meta-substitution reactions of benzene rings typically require complex synthetic steps and expensive catalysts, resulting in low synthetic efficiency and operational difficulties. In recent years, with continuous advancements in synthetic methods, the methods for synthesizing 1,3-substituted benzene rings have also been continuously optimized. For example, researchers at Xiamen University have developed a novel molybdenum catalyst capable of efficiently synthesizing 1,3-disubstituted and 1,3,5-trisubstituted benzene ring derivatives, overcoming the high cost and operational difficulties of traditional methods. However, this type of reaction is not applicable to electron-deficient 1,3-disubstituted substrates. This indicates that the synthesis technology of electron-deficient 1,3-substituted benzene rings urgently needs further exploration to meet the application needs of more fields. With the advancement of green chemistry and sustainable development, the development of environmentally friendly synthetic methods will also become a key focus of future research.

[0003] Despite continuous progress in the synthesis of 1,3-substituted benzene rings, challenges remain, including low synthesis efficiency, high cost and severe pollution, difficult operation, poor selectivity, and harsh reaction conditions. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, this invention provides a method for preparing electron-deficient 1,3-substituted benzene ring fluorinated compounds using a cobalt-photocatalyst. This process is mild, exhibits good regioselectivity, and requires only one step to efficiently obtain a series of electron-deficient substituted [1,3]-benzene ring fluorinated compounds.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The first aspect of the present invention provides a method for preparing electron-deficient 1,3-substituted benzene ring fluorinated compounds by photocobalt synergistic catalysis. The method includes the following steps: stirring and reacting enamine and fluorinated arylbutadiene in a solvent containing inorganic salt under the action of a composite catalyst and light irradiation to obtain electron-deficient 1,3-substituted benzene ring fluorinated compounds. The composite catalyst is composed of a mixture of a visible light catalyst and a metal catalyst. The visible light catalyst is a compound of formula (I) or formula (II): Among them, R1, R2, R3, R4, R5, R6, R7, R8, and R9 are groups with C1-C20 carbon atoms; Z is an anion; and A is a nitrogen atom or a carbon atom.

[0006] Furthermore, Z in formulas (I) and (II) can be any one of boron tetrafluoride anion, chloride ion, iodide ion, perchlorate ion, or hexafluorophosphate ion.

[0007] Furthermore, the metal catalyst is a cobalt oxime complex, and the cobalt oxime complex is any one of compounds of formula (III), formula (IV), formula (V), and formula (VI): Wherein, R10 and R11 are groups with C1-C20 carbon atoms; X is a halogen atom; and L is any one of p-toluenesulfonic acid group, trifluoromethanesulfonic acid group, nitrate group, carboxylate group, halide ion, hydroxyl group, amino group, azide group, and thiocyanate group.

[0008] Furthermore, the enamine compounds of formula (VII) or (VIII): Among them, R12, R13, R14, R15, R16, and R17 are groups with C1-C20 carbon atoms.

[0009] Furthermore, the fluorinated arylbutadiene is a compound of formula (IX) or formula (X): Among them, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, and R31 are groups with C1-C20 carbon atoms, and Y is any one of carbon, nitrogen, oxygen, and sulfur atoms.

[0010] Further, the inorganic salt is at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium fluoride, lithium nitrate, lithium phosphate, sodium acetate, cobalt acetate, and sodium bisulfite.

[0011] Furthermore, the molar ratio of the visible light catalyst, the metal catalyst, the enamine, the fluorinated arylbutadiene, and the inorganic salt is (0.01~0.05): (0.05~0.1): (1~2): (1~2): (1~2).

[0012] Further, the solvent is any one of acetonitrile, diethyl ether, tetrahydrofuran, dichloromethane, 1,4-dioxane, acetone, ethoxyethanol, o-xylene, m-xylene, p-xylene, and trifluorotoluene.

[0013] Furthermore, the light source used for the illumination is a Kessil lamp.

[0014] Furthermore, the wavelength of the illumination is 390 nm.

[0015] Furthermore, the stirring reaction refers to the reaction under magnetic rotor stirring, and the reaction time is 16~20 h.

[0016] A second aspect of the present invention provides an electron-deficient 1,3-substituted benzene ring fluorinated compound prepared by the above-described preparation method.

[0017] A third aspect of the present invention provides the application of the above-mentioned electron-deficient 1,3-substituted benzene ring fluorinated compound in the preparation of pharmaceutical intermediates.

[0018] Compared with the prior art, the beneficial effects of the present invention are: This invention provides a method for photo-induced synthesis of electron-deficient [1,3]-benzene ring fluorinated compounds. The method promotes the reaction of enamines with fluorinated arylbutadienes under the action of a composite catalyst, which is a mixture of a visible light catalyst and a metal catalyst. The advantages of using a photocatalyst are that the reaction process is safe and controllable, simplifying the preparation and production operations; using a Kessil lamp as the reaction light source is both safe and environmentally friendly, and possesses high energy utilization efficiency, enabling efficient conversion of light energy into chemical energy; the raw materials used are inexpensive and readily available, and the preparation process is simple. This process has mild conditions and good regioselectivity, requiring only one step to efficiently obtain a series of electron-deficient group-substituted [1,3]-benzene ring fluorinated compounds.

[0019] Specifically, the present invention has the following beneficial effects: 1. The reaction system is simple, the reaction process is safe and controllable, and the operation in the preparation and production process is simplified; 2. Using blue LEDs as the reaction energy source is safe, green, and has a high energy utilization rate, enabling efficient conversion of light energy into chemical energy; 3. The reactants are prepared from simple and commercially available raw materials and catalysts, which are inexpensive and readily available. Furthermore, these reactants do not require additional modification or protection before the reaction and can be used directly for preparation and production, simplifying the operation steps and shortening the reaction route. Moreover, the forward reaction rate is high, which significantly improves its production efficiency. 4. The required reaction conditions are mild, the steps are highly economical, and the environmental pollution is minimal, making it a promising method for industrial applications. Therefore, this method significantly reduces production costs and greatly expands the designability and application prospects of this type of compound. Detailed Implementation

[0020] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0021] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0022] The compounds and their derivatives involved in the following examples are named in accordance with the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, located in Columbus, Ohio) nomenclature systems.

[0023] Example 1: Preparation of compound 4-((4'-fluoro-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile In a dry 5 mL test tube, a methyltrimethylbenzene-substituted acridine salt (0.03 eq) of visible light catalyst, bromobis[(2,3-butanedione dioxime)-N,N'][4-(1,1-dimethylethyl)pyridine]-cobalt (0.1 eq), (E)-4-((2-(dimethylamino)vinyl)sulfonyl)benzonitrile (1 eq), K2HPO4 (1 eq), (E)-1-(4-fluorophenyl)-1,3-butadiene (1 eq), and 1 mL of anhydrous acetonitrile were added. The mixture was purged three times with argon gas and irradiated with a 390 nm Kessil lamp for 20 h. After the reaction was complete, the filtrate was evaporated to dryness and separated by column chromatography to obtain the target product 4-((4'-fluoro-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile, with a yield of 48%.

[0024] The structural formula of the target product 4-((4'-fluoro-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile is: The characterization analysis data of the product are as follows: 1H NMR (500 MHz, CDCl3) d 8.10 (t, J = 1.9 Hz, 1H), 8.09-8.07 (m, 2H), 7.93-7.87 (m, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.79-7.76 (m, 1H), 7.61 (t, J =7.8 Hz, 1H), 7.54 (dd, J = 8.7, 5.2 Hz, 2H), 7.20-7.14 (m, 2H). 13 C NMR (125 MHz, CDCl3) d 164.1, 162.1, 145.7, 142.1, 140.9, 134.9, 134.9, 133.1, 132.4, 130.2, 128.9, 128.9, 128.3, 126.6, 126.2, 117.1, 117.0, 116.2, 116.1. 19 F NMR (471 MHz, CDCl3) d -113.3. HRMS (ESI) m / z: [M+H] + calculated for 338.0646, found 338.0658. Example 2: Preparation of compound 4-((4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile The preparation method was the same as that in Example 1 for the preparation of 4-((4'-fluoro-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile, except that (E)-1-(4-trifluoromethylphenyl)-1,3-butadiene was used instead of (E)-1-(4-fluorophenyl)-1,3-butadiene. After the reaction was complete, the filtrate was evaporated to dryness and separated by column chromatography to obtain the target product 4-((4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile, with a yield of 52%.

[0025] The structural formula of the target product 4-((4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile is: The characterization analysis data of the product are as follows: 1 H NMR (500 MHz, CDCl3) d 8.16 (d, J = 1.9 Hz, 1H), 8.09 (d, J = 8.2Hz, 2H), 8.00-7.94 (m, 1H), 7.86-7.83 (m, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.73(d, J = 8.2 Hz, 2H), 7.70-7.63 (m, 3H). 13 C NMR (125 MHz, CDCl3) d 145.5, 141.6, 141.1, 133.2, 132.7, 130.4, 128.3, 127.6, 127.4, 126.5, 126.1, 126.1, 126.0, 126.0, 117.1, 117.0. 19 F NMR (471 MHz, CDCl3) d -62.6. HRMS (ESI) m / z: [M+H] + calculated for 388.0614, found 388.0625. Example 3: Preparation of compound 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile The preparation method was the same as that in Example 1 for the preparation of 4-((4'-fluoro-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile, except that (E)-1-(4-trifluoromethoxyphenyl)-1,3-butadiene was used instead of (E)-1-(4-fluorophenyl)-1,3-butadiene. After the reaction was complete, the filtrate was evaporated to dryness and separated by column chromatography to obtain the target product 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile, with a yield of 55%.

[0026] The structural formula of the target product 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile is: The characterization analysis data of the product are as follows: 1 H NMR (500 MHz, CDCl3) d 8.12 (d, J = 1.7 Hz, 1H), 8.09 (d, J = 8.2Hz, 2H), 7.94 (dd, J = 8.1, 1.8 Hz, 1H), 7.81 (dd, J = 7.5, 5.7 Hz, 3H), 7.63(t, J = 7.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H). 13 C NMR (125 MHz, CDCl3) d 149.5, 149.5, 145.6, 141.6, 141.0, 137.4, 133.1, 132.5, 130.3, 128.7, 128.3, 126.9, 126.3, 121.5, 117.1, 117.0. 19 F NMR (471 MHz, CDCl3) d -57.8. HRMS (ESI) m / z: [M+H] +calculated for 404.0563, found 404.0566. Example 4: Preparation of compound 4-((5'-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile The preparation method was the same as that in Example 1 for the preparation of 4-((4'-fluoro-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile, except that (E)-1-(2-methyl-5-fluorophenyl)-1,3-butadiene was used instead of (E)-1-(4-fluorophenyl)-1,3-butadiene. After the reaction was complete, the filtrate was evaporated to dryness and separated by column chromatography to obtain the target product 4-((5'-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile, with a yield of 54%.

[0027] The structural formula of the target product 4-((5'-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile is: The characterization analysis data of the product are as follows: 1 H NMR (500 MHz, CDCl3) d 8.11–8.06 (m, 2H), 7.95 (dt, J = 7.7, 1.6Hz, 1H), 7.90 (t, J = 1.8 Hz, 1H), 7.85-7.80 (m, 2H), 7.61 (t, J = 7.7 Hz, 1H), 7.57 (dt, J = 7.7, 1.5 Hz, 1H), 7.24 (dd, J = 8.5, 5.7 Hz, 1H), 7.01(td, J = 8.4, 2.8 Hz, 1H), 6.90 (dd, J = 9.2, 2.7 Hz, 1H), 2.16 (s, 3H). 13 C NMR (125 MHz, CDCl3) d161.9, 160.0, 145.7, 142.6, 142.6, 140.8, 140.7, 140.4, 134.5, 133.1, 132.1, 132.0, 130.7, 130.7, 129.7, 128.3, 128.3, 126.7, 117.1, 117.1, 116.3, 116.2, 115.1, 115.0, 19.5. 19 F NMR (471 MHz, CDCl3) d -117.2. HRMS (ESI) m / z: [M+H] + calculated for 352.0803, found 352.0804. Example 5: Preparation of compound ethyl 2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate The preparation method was the same as that in Example 1 for 4-((4'-fluoro-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile, except that (E)-1-(2,4-difluorophenyl)-1,3-butadiene was used instead of (E)-1-(4-fluorophenyl)-1,3-butadiene, and (E)-3-(dimethylamino)acrylate was used instead of (E)-4-((2-(dimethylamino)vinyl)sulfonyl)benzonitrile. After the reaction was complete, the filtrate was evaporated to dryness and separated by column chromatography to obtain the target product ethyl 2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate, with a yield of 65%.

[0028] The structural formula of the target product ethyl 2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate is as follows: The characterization analysis data of the product are as follows: 1 H NMR (500 MHz, CDCl3) d 8.17 (q, J = 1.7 Hz, 1H), 8.05 (dt, J = 7.8, 1.4 Hz, 1H), 7.69 (dq, J = 7.9, 1.6 Hz, 1H), 7.51 (t,J = 7.8 Hz, 1H), 7.43(td, J = 8.7, 6.4 Hz, 1H), 7.02-6.88 (m, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.41(t, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, CDCl3) d 166.4, 163.6, 163.5, 161.6, 161.5, 160.8, 160.7, 158.8, 158.7, 135.2, 133.3, 133.3, 131.5, 131.5, 131.5, 131.4, 131.0, 129.9, 129.9, 128.8, 128.6, 124.5, 124.5, 124.4, 124.4, 111.8, 111.8, 111.7, 111.6, 104.7, 104.5, 104.3, 61.2, 14.3. 19 F NMR (471 MHz, CDCl3) d -110.6, -113.5. HRMS (ESI) m / z: [M+H] + calculated for 263.0879, found 263.0879. Example 6: Preparation of compound N-(pyridin-3-yl)-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide The preparation method was the same as that in Example 1 for the preparation of 4-((4'-fluoro-[1,1'-biphenyl]-3-yl)sulfonyl)benzonitrile, except that (E)-1-(4-trifluoromethoxyphenyl)-1,3-butadiene was used instead of (E)-1-(4-fluorophenyl)-1,3-butadiene, and (E)-3-(dimethylamino)-N-(pyridin-3-yl)acrylamide was used instead of (E)-4-((2-(dimethylamino)vinyl)sulfonyl)benzonitrile. After the reaction was complete, the filtrate was evaporated to dryness and separated by column chromatography to obtain the target product N-(pyridin-3-yl)-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide, with a yield of 50%.

[0029] The structural formula of the target product N-(pyridin-3-yl)-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide is: The characterization analysis data of the product are as follows: 1 H NMR (500 MHz, CDCl3) d 8.70 (d, J = 2.6 Hz, 1H), 8.41 (dd, J = 4.8, 1.5 Hz, 1H), 8.33 (dt, J = 8.4, 2.7, 1.5 Hz, 1H), 8.09 (t, J = 1.9 Hz, 1H),7.99 (s, 1H), 7.86 (dt, J = 7.7, 1.5 Hz, 1H), 7.77 (dt, J = 7.8, 1.4 Hz, 1H),7.67-7.62 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.37-7.31 (m, 3H). 13 C NMR (125 MHz, CDCl3) d164.7, 149.7, 149.4, 149.1, 145.7, 143.7, 141.5, 140.8, 138.7, 135.0, 130.9, 129.5, 128.6, 127.7, 126.1, 126.0, 121.4. 19 F NMR (471 MHz, CDCl3) d -57.8. HRMS (ESI) m / z: [M+H] + calculated for 359.1002, found 359.1002. The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. For those skilled in the art, various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and these variations still fall within the protection scope of the present invention.

Claims

1. A method for preparing electron-deficient 1,3-substituted benzene ring fluorinated compounds by photocobalt co-catalysis, characterized in that, The method includes the following steps: stirring and reacting enamine and fluorinated arylbutadiene in a solvent containing inorganic salt under the action of a composite catalyst and light to obtain an electron-deficient 1,3-substituted benzene ring fluorinated compound; The composite catalyst is composed of a mixture of a visible light catalyst and a metal catalyst. The visible light catalyst is a compound of formula (I) or formula (II): Among them, R1, R2, R3, R4, R5, R6, R7, R8, and R9 are groups with C1-C20 carbon atoms; Z is an anion; and A is a nitrogen atom or a carbon atom.

2. The method for preparing electron-deficient 1,3-substituted benzene ring fluorinated compounds by photocobalt synergistic catalysis according to claim 1, characterized in that, In formulas (I) and (II), Z can be any one of boron tetrafluoride anion, chloride ion, iodide ion, perchlorate ion, or hexafluorophosphate ion.

3. The method for preparing electron-deficient 1,3-substituted benzene ring fluorinated compounds by photocobalt synergistic catalysis according to claim 1, characterized in that, The metal catalyst is a cobalt oxime complex, and the cobalt oxime complex is any one of compounds of formula (III), (IV), (V), and (VI): Wherein, R10 and R11 are groups with C1-C20 carbon atoms; X is a halogen atom; and L is any one of p-toluenesulfonic acid group, trifluoromethanesulfonic acid group, nitrate group, carboxylate group, halide ion, hydroxyl group, amino group, azide group, and thiocyanate group.

4. The method for preparing electron-deficient 1,3-substituted benzene ring fluorinated compounds by photocobalt synergistic catalysis according to claim 1, characterized in that, The enamine compounds of formula (VII) or (VIII): Among them, R12, R13, R14, R15, R16, and R17 are groups with C1-C20 carbon atoms.

5. The method for preparing electron-deficient 1,3-substituted benzene ring fluorinated compounds by photocobalt synergistic catalysis according to claim 1, characterized in that, The fluorinated arylbutadiene is a compound of formula (IX) or formula (X): Among them, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, and R31 are groups with C1-C20 carbon atoms, and Y is any one of carbon, nitrogen, oxygen, and sulfur atoms.

6. The method for preparing electron-deficient 1,3-substituted benzene ring fluorinated compounds by photocobalt synergistic catalysis according to claim 1, characterized in that, The inorganic salt is at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium fluoride, lithium nitrate, lithium phosphate, sodium acetate, cobalt acetate, and sodium bisulfite.

7. The method for preparing electron-deficient 1,3-substituted benzene ring fluorinated compounds by photocobalt synergistic catalysis according to claim 1, characterized in that, The molar ratio of the visible light catalyst, metal catalyst, enamine, fluorinated arylbutadiene, and inorganic salt is (0.01~0.05): (0.05~0.1): (1~2): (1~2): (1~2).

8. The method for preparing electron-deficient 1,3-substituted benzene ring fluorinated compounds by photocobalt synergistic catalysis according to claim 1, characterized in that, The solvent is any one of acetonitrile, diethyl ether, tetrahydrofuran, dichloromethane, 1,4-dioxane, acetone, ethoxyethanol, o-xylene, m-xylene, p-xylene, and trifluorotoluene.

9. An electron-deficient 1,3-substituted benzene ring fluorinated compound prepared by the preparation method according to any one of claims 1-8.

10. The use of an electron-deficient 1,3-substituted benzene ring fluorinated compound as described in claim 9 in the preparation of pharmaceutical intermediates.

Images