Method for generating beta-ketonitrile compound by photocatalyzing ring opening of isoxazole
Through the photocatalytic isoxazole ring opening method, the problem of using toxic reagents and harsh reaction conditions in the existing β-ketonitrile synthesis methods is solved, and efficient, economical and environmentally friendly β-ketonitrile synthesis is achieved, with high yield and suitable for sensitive conditions.
Patent Information
- Application Number
- CN202510161622.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-13
- Publication Date
- 2025-05-30
AI Technical Summary
The existing methods for synthesizing β-ketonitrile compounds have problems such as the use of toxic agents, the need for a strong alkali or acidic environment, the narrow substrate range and the harsh reaction conditions.
By photocatalyzing the opening of isoxazole ring, using 9-thioxonone as the photocatalyst, the reaction was carried out under an inert gas atmosphere, magnetic stirring was performed by 390 nm, 10 W light and room temperature, and finally the β-ketonitrile compound was separated by rapid column chromatography.
It has achieved efficient synthesis of β-ketonitrile compounds, with mild reaction conditions, good atomic economy, and a yield of up to 95%. It is suitable for ketonitrile synthesis with sensitive acid or alkaline conditions.
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Figure CN120058557A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of organic chemical synthesis, and particularly to a new method for generating β-ketonitrile compounds by photocatalytic ring-opening of isoxazoles. Background Art
[0002] β-Ketonitrile compounds are widely used in medicine, pesticides, and materials science due to their unique chemical structures and have important research and commercial values. β-Ketonitrile compounds can participate in various chemical reactions, such as Michael addition, cyclization reactions, etc., to construct multi-functionalized organic molecules, providing important methods for synthesizing the skeleton structures of natural products, pharmaceutical intermediates, etc.
[0003] Currently, the main methods for synthesizing β-ketonitrile compounds are as follows: synthesizing β-ketonitrile by acylation reaction of acrylonitrile anion with non-activated esters (Org. Lett. 2006, 8, 1161 - 1163), synthesizing β-ketonitrile by replacing α-haloketone with highly toxic cyanide anion (Adv. Synth. Catal. 2022, 364, 87 - 93), copper-catalyzed oxidative coupling of aromatic alcohols and acetonitrile to synthesize β-ketonitrile (Org. Lett. 2014, 16, 350 - 353), Pd-catalyzed carbonylation reaction of carbon monoxide, aryl halides and (trimethylsilyl)acetonitrile or tert-butyl cyanoacetate to synthesize β-ketonitrile (Chem. Eur. J. 2014, 20, 9534 - 9538; J. Org. Chem. 2016, 81, 1358 - 1366), under the catalysis of BF 3 ·OEt 2 synthesize β-ketonitrile by nucleophilic addition and 1,2-hydrogen transfer of aromatic aldehydes and diazoacetonitrile (Eur. J. Org. Chem. 2014, 6380 - 6384), NHC-catalyzed radical coupling reaction of aldehydes and azobisisobutyronitrile to synthesize β-ketonitrile (Org. Lett. 2023, 25, 3325 - 3329), Pd-catalyzed addition of organoboron reagents to dinitriles in an acidic environment to synthesize β-ketonitrile (J. Org. Chem. 2021, 86, 861 - 867), etc. However, the above strategies all have some deficiencies, such as the need for toxic carbon monoxide, the need to use special cyanide reagents, the need for strong bases or acidic environments, narrow substrate scope, and relatively harsh reaction conditions. Therefore, it is still of great value to develop a new strategy to achieve the convenient and efficient construction of this potentially bioactive skeleton structure. Summary of the Invention
[0004] The present invention provides a new method for generating β-ketonitrile compounds by photocatalytic ring-opening of isoxazoles, which has the advantages of simple operation, economic and environmental protection, good atom economy, mild conditions, good substrate generality, etc.
[0005] To solve the technical problems of the present invention, the technical solution proposed is as follows: A new method for generating β-ketonitriles by photocatalytic ring-opening of isoxazoles, comprising the following steps:
[0006] Step 1: Under an inert gas atmosphere, an isoxazole compound (Formula I), tris(trimethylsilyl)silane, 9-thioxanthone (photocatalyst), and a solvent are successively added to a reaction tube and stirred magnetically until homogeneous to obtain a mixture;
[0007] Step 2: Under an inert gas atmosphere, the above mixture is stirred magnetically at 390 nm, 10 W light irradiation and room temperature until the reaction is complete, and the β-ketonitrile compound (Formula II) is separated from the reaction mixture by flash column chromatography.
[0008] The specific reaction route is as follows:
[0009]
[0010] Wherein R 1 is: 4-methylphenyl, 3-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, 4-biphenyl, 4-methoxyphenyl, 3,5-bis(trifluoromethyl)phenyl, benzothiazole, n-butyl, 2-hydroxyethyl, naphthalen-1-yl, pyridin-3-yl, thiophen-3-yl, 1,2-methylenedioxyphenyl, and other alkyl groups; R 2 is: hydrogen, ethyl, benzene.
[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 any one of ethyl acetate, ethylene glycol dimethyl ether, acetone, diethyl ether, acetonitrile, N,N-dimethylformamide, and tetrahydrofuran.
[0013] Preferably, in Step 1, the photocatalyst is 9-thioxanthone.
[0014] Preferably, in Step 1, the molar ratio of the isoxazole compound, tris(trimethylsilyl)silane, and 9-thioxanthone is 1:1.1:0.05.
[0015] Preferably, in Step 2, the light source is a 390 nm, 10 W purple lamp, and the reaction temperature is room temperature.
[0016] Preferably, in Step 2, the separation conditions for the flash column chromatography are: passing the reaction product through a column packed with 200-300 mesh silica gel, and using a mixed solvent of ethyl acetate and petroleum ether as the eluent for column separation to obtain a pure β-ketonitrile compound.
[0017] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0018] 1. The present invention provides a new method for synthesizing β-ketonitrile compounds, with a clean reaction system, high conversion rate, and easy separation of products.
[0019] 2. By optimizing the reaction conditions, the present invention can obtain the target compound with a high yield, up to 95% at the highest, with good reaction generality and relatively high atom economy.
[0020] 3. It is applicable to the synthesis of ketonitriles sensitive to acidic or basic conditions and is an important supplement to the synthesis method of β-ketonitrile compounds. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1 is the nuclear magnetic resonance 1 1H spectrum of compound 2a;
[0022] Figure 2 is the nuclear magnetic resonance 13 13C spectrum of compound 2a;
[0023] Figure 3 is the nuclear magnetic resonance 1 1H spectrum of compound 2b;
[0024] Figure 4 is the nuclear magnetic resonance 13 13C spectrum of compound 2b;
[0025] Figure 5 is the nuclear magnetic resonance 1 1H spectrum of compound 2c;
[0026] Figure 6 is the nuclear magnetic resonance 13 13C spectrum of compound 2c;
[0027] Figure 7 is the nuclear magnetic resonance 1 1H spectrum of compound 2d;
[0028] Figure 8 is the nuclear magnetic resonance 13 13C spectrum of compound 2d. DETAILED DESCRIPTION OF THE INVENTION
[0029] In order to make the objectives, technical solutions and advantages of the present invention more clear and understandable, the present invention will be further described in detail below with reference to 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 β-ketonitrile compounds can be synthesized. The specific structural formula of the target product is as follows:
[0031]
[0032] Example 1
[0033]
[0034] Under a nitrogen atmosphere, isoxazole compound 1a (31.1 mg, 0.1 mmol, 1.0 equiv), tris(trimethylsilyl)silane (27.3 mg, 0.11 mmol, 1.1 equiv), Thioxanthen-9-one (photocatalyst) (1 mg, 0.1 mmol, 0.05 equiv), and solvent ethyl acetate (1 mL) were successively added to a reaction tube and stirred magnetically until homogeneous to obtain a mixture. The above mixture was stirred magnetically at 390 nm, 10 W light irradiation, and room temperature until the reaction was complete. The pure target compound 2a was separated from the reaction mixture by flash column chromatography, and the separation yield was 66%.
[0035] The characterization results of compound 2a are as Figures 1-2 shown, where 1 H NMR (400 MHz, CDCl 3 ) δ 6.19 (dd, J = 5.7, 3.1 Hz, 1H), 5.89 (dd, J = 5.7, 2.9 Hz, 1H), 4.30 (td, J = 6.1, 1.0 Hz, 2H), 3.53 (s, 2H), 3.15 (qd, J = 2.6, 1.6 Hz, 1H), 2.95 - 2.92 (m, 2H), 2.91 (t, J = 6.1 Hz, 2H), 1.89 (ddd, J = 11.7, 9.3, 3.7 Hz, 1H), 1.43 (dq, J = 8.3, 2.0 Hz, 1H), 1.37 (ddd, J = 11.8, 4.2, 2.7 Hz, 1H), 1.30 - 1.22 (m, 1H). 13 C NMR (100 MHz, CDCl 3 ):δ 195.0, 174.6, 138.1, 132.2, 113.5, 58.5, 49.7, 45.8, 43.2, 42.6, 41.2, 32.4, 29.3.
[0036] Example 2
[0037]
[0038] Under a nitrogen atmosphere, isoxazole compound 1b (29.5 mg, 0.1 mmol, 1.0 equiv), tris(trimethylsilyl)silane (27.3 mg, 0.11 mmol, 1.1 equiv), Thioxanthen-9-one (9-thioxanthone, photocatalyst) (1 mg, 0.1 mmol, 0.05 equiv), and the solvent ethyl acetate (1 mL) were successively added to a reaction tube and stirred magnetically until homogeneous to obtain a mixture; the above mixture was stirred magnetically at 390 nm, 10 W light irradiation, and room temperature until the reaction was complete, and the pure target compound 2b was separated from the reaction mixture by flash column chromatography with a separation yield of 72%.
[0039] The characterization results of compound 2b are as Figures 3-4 shown, where 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 - 7.93 (m, 2H), 7.60 - 7.51 (m, 1H), 7.47 - 7.39 (m, 2H), 4.60 (t, J = 6.1 Hz, 2H), 3.58 (s, 2H), 3.07 (t, J = 6.1 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ):δ 195.1, 166.4, 133.5, 129.7, 129.6, 128.6, 113.6, 59.1, 41.2, 32.5.
[0040] Example 3
[0041]
[0042] Under a nitrogen atmosphere, isoxazole compound 1c (30.1 mg, 0.1 mmol, 1.0 equiv), tris(trimethylsilyl)silane (27.3 mg, 0.11 mmol, 1.1 equiv), Thioxanthen-9-one (9-thioxanthone, photocatalyst) (1 mg, 0.1 mmol, 0.05 equiv), and the solvent ethyl acetate (1 mL) were successively added to a reaction tube and stirred magnetically until homogeneous to obtain a mixture; the above mixture was stirred magnetically at 390 nm, 10 W light irradiation, and room temperature until the reaction was complete, and the pure target compound 2c was separated from the reaction mixture by flash column chromatography with a separation yield of 45%.
[0043] The characterization results of compound 2c are as Figures 7-8 shown, where 1 H NMR (400 MHz, DMSO-d 6) δ 7.91 - 7.87 (m, 2H), 7.87 - 7.83 (m, 2H), 4.65 (s, 2H), 4.31 (s, 2H). 13 C NMR (100 MHz, DMSO-d6): δ 194.6, 167.7, 135.4, 131.9, 124.0, 115.4, 46.4, 30.6.
[0044] Example 4
[0045]
[0046] Under a nitrogen atmosphere, isoxazole compound 1d (27.9 mg, 0.1 mmol, 1.0 equiv), tris(trimethylsilyl)silane (27.3 mg, 0.11 mmol, 1.1 equiv), Thioxanthen-9-one (9-thioxanthone, photocatalyst) (1 mg, 0.1 mmol, 0.05 equiv), and the solvent ethyl acetate (1 mL) were successively added to a reaction tube and stirred magnetically until homogeneous to obtain a mixture; the above mixture was stirred magnetically at 390 nm, 10 W light irradiation, and room temperature until the reaction was complete, and the pure target compound 2d was separated from the reaction mixture by flash column chromatography with a separation yield of 48%.
[0047] The characterization results of compound 2d are as Figures 7-8 shown, where 1 H NMR (400 MHz, CDCl 3 ) δ 8.26 - 8.16 (m, 1H), 8.05 - 7.98 (m, 1H), 7.67 - 7.57 (m, 2H), 4.44 (s, 2H). 13 C NMR (100 MHz, CDCl 3 ):δ 182.6, 162.4, 152.9, 137.5, 128.5, 127.4, 125.6, 122.4, 112.9, 28.8.
[0048] Examples 5 - 21
[0049] Examples 5 - 21 are basically the same as Example 1, except that the substituents R 1 and R 2 in the isoxazole compounds are different from each other. The specific structures of the isoxazole compounds are shown in the following table:
[0050] Table 1 Examples 5 - 21
[0051]
[0052]
[0053]
[0054] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.
Claims
1. A method for synthesizing β-ketonitrile compounds by visible light catalysis, characterized in that: Under light conditions, under the action of diaryl ketone photocatalyst and tris(trimethylsilyl)silane, the isoxazole compound undergoes a ring-opening reaction to obtain a β-ketonitrile compound.
2. The method for generating β-ketonitrile compounds by photocatalytic isoxazole ring opening according to claim 1, characterized in that: The following steps are involved: Step 1: under an inert gas atmosphere, add an isoxazole compound (Formula 1), tris(trimethylsilyl)silane, 9-thioxanthone (photocatalyst) and a solvent into a reaction tube in sequence and stir them evenly with a magnetic force to obtain a mixture; Step 2: Under an inert gas atmosphere, the mixture is magnetically stirred at 390 nm, 10 W light and room temperature until the reaction is complete, and the β-ketonitrile compound (Formula 2) is separated from the reaction mixture by rapid column chromatography. The specific reaction route is as follows:
3. The method for generating β-ketonitrile compounds by photocatalytic isoxazole ring opening 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 generating β-ketonitrile compounds by photocatalytic isoxazole ring opening according to claim 1, characterized in that: The photocatalyst is 9-thioxanthone.
5. The method for generating β-ketonitrile compounds by photocatalytic isoxazole ring opening according to claim 1, characterized in that: The solvent is any one of ethyl acetate, ethylene glycol dimethyl ether, acetone, ethyl ether, acetonitrile, N,N-dimethylformamide and tetrahydrofuran.
6. The method for generating β-ketonitrile compounds by photocatalytic isoxazole ring opening according to claim 1, characterized in that: The reaction temperature is room temperature; the reaction time is 1-12h.
7. The method for generating β-ketonitrile compounds by photocatalytic isoxazole ring opening according to claim 1, characterized in that: The molar ratio of the isoxazole compound, tris(trimethylsilyl)silane and 9-thioxanthone is 1:1.1:0.
05.
8. The method for generating β-ketonitrile compounds by photocatalytic isoxazole ring opening according to claim 1, characterized in that: The specific reaction route is as follows: Where R 1 is: 4-methylphenyl, 3-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, 4-biphenyl, 4-methoxyphenyl, 3,5-bis(trifluoromethyl)phenyl, benzothiazole, n-butyl, 2-hydroxyethyl, naphth-1-yl, pyridin-3-yl, thien-3-yl, 1,2-methylenedioxyphenyl, and other alkyl groups; R 2 For: hydrogen, ethyl, benzene.