Process for the synthesis of methoxyspiroindolpyrrolidinone compounds

Abstract

The application belongs to the technical field of fine organic synthesis, and particularly relates to a synthesis method of methoxy spiroindole pyrrolidinone compounds. The application takes substituted indole propionamide as a starting material, and the desired methoxy spiroindole pyrrolidinone compound can be obtained through de-arylation oxygen amination reaction of the indole. The method has the advantages of few reaction steps, mild reaction conditions and simple operation, and the synthesized compound shows excellent inhibitory activity on specific plant fungi.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of fine organic synthesis, and particularly relates to a synthesis method of a methoxy spiroindole pyrrolidinone compound. BACKGROUND

[0002] The information disclosed in this BACKGROUND section is only for the purpose of increasing the understanding of the general background of the application and does not necessarily constitute an admission by the patent applicant(s) that this information constitutes prior art.

[0003] Nitrogen-containing spiro compounds, especially amide spiro compounds, have been used to construct a variety of bioactive and complex molecules as building blocks due to their novel three-dimensional structure and unique medical and pesticidal activity. In the de-aromatization functionalization reaction of aromatic hydrocarbons, amideization by de-aromatization of indole derivatives is a commonly used method for efficient construction of spiro amide compounds. As an important part of spiro amide compounds, there is only one example of a literature report on the synthesis method of spiroindole pyrrolidinone (Chem. Commun., 2020, 56, 8436-8439). Under the combined action of Ru(bpy)3Cl2•6H2O as a catalyst and high-valence iodine BI-OAc as an oxidant, de-aromatization oxamination of indole occurs to obtain a methoxy-substituted spiroindole pyrrolidinone compound under light conditions. The problems of this route are: 1. Due to the low light absorption and light transmission rate of such a photocatalytic reaction, the reaction is difficult to scale up, and only milligram-level target compounds can be obtained; 2. The [Ru] photocatalyst in the reaction is expensive, and the synthesis process of the oxidant BI-OAc is complex, which further limits the application of the reaction in terms of cost; 3. The reaction yield is only 53%. In addition, the pesticidal and medical activity of such compounds has not been reported in the literature. SUMMARY

[0004] In order to solve the problems of the prior art, the purpose of the present application is to provide a synthesis method of a methoxy spiroindole pyrrolidinone compound. The present application uses a substituted indole propionamide as a starting material, and the desired methoxy spiroindole pyrrolidinone compound can be obtained through a de-aromatization oxamination reaction of indole. This method has the advantages of fewer reaction steps, mild reaction conditions, and simple operation. The synthesized compound exhibits excellent inhibitory activity against specific plant fungi.

[0005] In order to achieve the above-mentioned purpose, the present application is realized by the following technical scheme:

[0006] The synthesis method of the methoxy spiroindole pyrrolidinone compound comprises the following contents:

[0007] The substituted indole propionamide is subjected to de- aromatization oxygen amination reaction under the action of an oxidant and a base to obtain a methoxy substituted spiroindole pyrrolidinone compound, and the synthesized compound has excellent inhibitory activity on specific plant fungi.

[0008] Preferably, in the synthesis reaction of the methoxy substituted spiroindole pyrrolidinone compound, the temperature is 40-100 DEG C, and the time is 6-20 h.

[0009] Preferably, in the synthesis reaction of the methoxy substituted spiroindole pyrrolidinone compound, the oxidant comprises at least one of NIS (N-iodosuccinimide) and NBS (N-bromosuccinimide).

[0010] Preferably, in the synthesis reaction of the methoxy substituted spiroindole pyrrolidinone compound, the base comprises at least one of potassium carbonate, sodium carbonate and cesium carbonate.

[0011] Preferably, in the synthesis reaction of the methoxy substituted spiroindole pyrrolidinone compound, the solvent is a mixed solvent of one of chloroform, dichloromethane and DMF (N, N-dimethylformamide) and methanol.

[0012] Preferably, in the synthesis reaction of the methoxy substituted spiroindole pyrrolidinone compound, the molar ratio of the substituted indole propionamide, the oxidant and the base is 1: (2-2.5) : (2-2.5).

[0013] Preferably, the plant fungi is at least one of tomato early blight, cucumber gray mold, wheat scab, rice blast, pepper blight, rice sheath blight and rape sclerotinia.

[0014] The beneficial effects of the one or more technical solutions of the application are as follows:

[0015] The substituted indole propionamide is subjected to de- aromatization oxygen amination reaction under the action of an oxidant and a base to obtain a methoxy substituted spiroindole pyrrolidinone compound, and the synthesized compound has excellent inhibitory activity on specific plant fungi. BRIEF DESCRIPTION OF DRAWINGS

[0016] The drawings accompanying the specification of the application form a part of the application and serve to provide further understanding of the application, the illustrative embodiments of the application and their descriptions serve to explain the application, and do not constitute improper limitations on the application.

[0017] Figure 1 Nuclear magnetic hydrogen spectrum of the methoxy substituted spiroindole pyrrolidinone compound synthesized by the application. DETAILED DESCRIPTION

[0018] In order for those skilled in the art to more clearly understand the technical solutions of the present application, the technical solutions of the present application will be described below in detail with specific examples and comparative examples.

[0019] Example 1:

[0020]

[0021] Under the protection of nitrogen, 50 mL of dichloroethane, 10 mL of methanol, substituted indole propionamide (3.48 g, 10 mmol), N-iodosuccinimide (4.95 g, 22 mmol) and potassium carbonate (2.76 g, 20 mmol) were mixed into a reaction system, and stirred rapidly at 70°C for 12 hours. After the reaction was completed, 20 mL of deionized water was added to the reaction system, and the organic phase was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain 3.31 g of product with a yield of 87%.

[0022] The nuclear magnetic resonance hydrogen spectrum of the methoxy-substituted spiroindole pyrrolidinone compound is shown in Figure 1 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.28 - 7.07 (m, 4H), 6.60 - 6.51 (m, 2H), 5.84 (s, 1H), 3.05 (s, 3H), 2.96 (ddd, J = 22.3, 11.2, 5.2 Hz, 2H), 2.89 - 2.74 (m, 1H), 2.61 - 2.47 (m, 1H), 1.07 (s, 9H). Example 2:

[0023]

[0024] Under the protection of nitrogen, 50 mL of dichloroethane, 10 mL of methanol, substituted indole propionamide (3.48 g, 10 mmol), N-iodosuccinimide (4.95 g, 22 mmol) and potassium carbonate (2.76 g, 20 mmol) were mixed into a reaction system, and stirred rapidly at 60°C for 12 hours. After the reaction was completed, 20 mL of deionized water was added to the reaction system, and the organic phase was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain 3.02 g of product with a yield of 80%.

[0025] Example 3:

[0026]

[0027] Substituted indole propionamide (3.48 g, 10 mmol), N-bromosuccinimide (3.92 g, 22 mmol) and potassium carbonate (2.76 g, 20 mmol) were mixed in 50 mL dichloroethane and 10 mL methanol under nitrogen protection, and stirred rapidly at 70°C for 12 hours. After the reaction was completed, 20 mL of deionized water was added to the reaction system, and the organic phase was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain 2.57 g of product with a yield of 68%.

[0028] Example 4:

[0029]

[0030] Substituted indole propionamide (3.48 g, 10 mmol), N-bromosuccinimide (3.92 g, 22 mmol) and potassium carbonate (2.76 g, 20 mmol) were mixed in 50 mL dichloroethane and 10 mL methanol under nitrogen protection, and stirred rapidly at 70°C for 12 hours. After the reaction was completed, 20 mL of deionized water was added to the reaction system, and the organic phase was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain 2.57 g of product with a yield of 68%.

[0031] Example 5:

[0032]

[0033] Substituted indole propionamide (3.48 g, 10 mmol), N-bromosuccinimide (3.92 g, 22 mmol) and potassium carbonate (2.76 g, 20 mmol) were mixed in 50 mL dichloroethane and 10 mL methanol under nitrogen protection, and stirred rapidly at 70°C for 12 hours. After the reaction was completed, 20 mL of deionized water was added to the reaction system, and the organic phase was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain 2.57 g of product with a yield of 68%.

[0034] Bactericidal activity test:

[0035] In view of the potential biological activity of the spiroindolyl pyrrolidinone compounds, we tested the fungicidal activity of the compound synthesized in Example 1 (Table 1). Common plant fungi including tomato early blight, cucumber gray mold, wheat scab, rice blast, pepper pythium, rice sheath blight, and cabbage sclerotinia were included in the test. The results of the fungicidal activity of the product (in vitro test (50 μg / mL), inhibition rate ± standard deviation (%)) showed that, compared with the reference agents of chlorothalonil and carbendazim, the spiroindolyl pyrrolidinone compounds exhibited inhibitory activity against the test fungi, especially against tomato early blight, wheat scab, pepper pythium, and cabbage sclerotinia, and exhibited inhibitory effects comparable to or even superior to the reference agents.

[0036]

[0037] The preferred embodiments of the present application have been described above with the specific examples. The present application is not limited to the above examples, and various modifications and changes can be made by those skilled in the art. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for synthesizing a methoxy-spiroindolpyrrolidinone compound, comprising the following steps: The substituted indole propionamide is subjected to de- aromatization oxygen amination reaction under the action of an oxidant and a base to obtain a methoxy substituted spiroindole pyrrolidinone compound, the reaction is carried out in a solvent, the oxidant is one of NIS and NBS, the solvent is a mixed solvent of one of chloroform and dichloroethane and methanol, the synthesized compound has excellent inhibitory activity on specific plant fungi; the substituted indole propionamide is , and the methoxy substituted spiroindole pyrrolidinone compound is .

2. The method of claim 1, wherein, In the synthesis reaction of the methoxy-substituted-spiroindolpyrrolidinone compound, the reaction temperature is 40-100 ℃, and the reaction time is 6-20 h.

3. The method of claim 1, wherein, In the synthesis reaction of the methoxy-substituted-spiroindolpyrrolidinone compound, the base is one of potassium carbonate and sodium carbonate.

4. The method of claim 1, wherein, In the synthesis reaction of the methoxy-substituted-spiroindolpyrrolidinone compound, the molar ratio of the substituted indole propionamide, the oxidant and the base is 1: (2-2.5) : (2-2.5).

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