Synthesis method of methoxy spiroindole pyrrolidone compound

Abstract

The invention belongs to the technical field of fine organic synthesis, and particularly relates to a synthetic method of a methoxy spiroindole pyrrolidone compound. According to the method, substituted indole propionamide is used as a starting material, the expected methoxy spiroindole pyrrolidone compound can be obtained through the dearomatization and oxygen amination reaction of indole, and the method has the advantages of being few in reaction step, mild in reaction condition and simple and easy to operate; the synthesized compound shows excellent inhibitory activity on specific plant fungi.

Description

Technical Field

[0001] The invention belongs to the technical field of fine organic synthesis, and in particular relates to a method for synthesizing a methoxyspiroindole pyrrolidone compound. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] As building blocks, nitrogen-containing spiro compounds, especially amide spiro compounds, have been used to construct a variety of biologically active and complex molecules due to their novel three-dimensional structures and unique pharmaceutical and pesticide activities. In the dearomatization functionalization reaction of aromatic hydrocarbons, dearomatization amidation through indole derivatives is a commonly used and efficient method to construct spiroamide compounds. As the most important part of spiroamide compounds, the synthesis method of spiroindole pyrrolidone has only been reported in one literature (Chem. Commun., 2020, 56, 8436−8439). Under light conditions, in the presence of Ru(bpy)3Cl2•6H2O as a catalyst and high-valent iodine BI-OAc as an oxidant, dearomatization oxidative amination of indole occurs to obtain methoxy-substituted spiroindole pyrrolidone compounds. The problems with this route are: 1. Due to the low absorbance and transmittance of this type of photocatalytic reaction, it is difficult to scale up the process and the target compound can only be obtained at the milligram level; 2. The [Ru] photocatalyst in this reaction is expensive, and the synthesis process of the oxidant BI-OAc is complicated, which further limits the application of this reaction in terms of cost; 3. The reaction yield is low, only 53%. In addition, the pesticide and pharmaceutical activity of this type of compound has not been reported in the literature. Summary of the invention

[0004] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a method for synthesizing a methoxyspiroindole pyrrolidone compound. The present invention uses substituted indole propionamide as a starting material, and undergoes a dearomatization oxyamination reaction of indole to obtain the desired methoxyspiroindole pyrrolidone compound. The method has the advantages of fewer reaction steps, mild reaction conditions, and simple and easy operation. The synthesized compound exhibits excellent inhibitory activity against specific plant fungi.

[0005] In order to achieve the above object, the present invention is implemented through the following technical solutions: The synthesis method of a methoxyspiroindole pyrrolidone compound comprises the following contents: The substituted indole propionamide undergoes dearomatization oxyamination reaction under the action of an oxidant and a base to obtain a methoxy-substituted spiroindole pyrrolidone compound. The synthesized compound has excellent inhibitory activity against specific plant fungi.

[0006] Preferably, in the synthesis reaction of the methoxy-substituted spiroindole pyrrolidone compound, the temperature is 40-100° C. and the time is 6-20 h.

[0007] Preferably, in the synthesis reaction of the methoxy-substituted spiroindole pyrrolidone compound, the oxidant comprises at least one of NIS (N-iodosuccinimide) and NBS (N-bromosuccinimide).

[0008] Preferably, in the synthesis reaction of the methoxy-substituted spiroindole pyrrolidone compound, the base comprises at least one of potassium carbonate, sodium carbonate and cesium carbonate.

[0009] Preferably, in the synthesis reaction of the methoxy-substituted spiroindole pyrrolidone compound, the solvent is a mixed solvent of methanol and one of chloroform, dichloromethane, DMF (N,N-dimethylformamide).

[0010] Preferably, in the synthesis reaction of the methoxy-substituted spiroindole pyrrolidone compound, the molar ratio of the substituted indolepropionamide, the oxidant, and the base is 1:(2-2.5):(2-2.5).

[0011] Preferably, the plant fungus is at least one of tomato early blight, cucumber gray mold, wheat gibberella, rice blast, pepper phytophthora, rice sheath blight, and rapeseed sclerotium.

[0012] The beneficial effects achieved by one or more technical solutions of the present invention are as follows: The invention uses substituted indole propionamide as a starting material, and under the action of an oxidant and a base, dearomatization oxyamination reaction occurs to obtain a methoxy-substituted spiroindole pyrrolidone compound. The synthesized compound has excellent inhibitory activity against specific plant fungi. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0014] Figure 1 The present invention provides a hydrogen nuclear magnetic spectrum of the methoxy-substituted spiroindole pyrrolidone compound synthesized by the present invention. DETAILED DESCRIPTION

[0015] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in combination with specific embodiments and comparative examples.

[0016] Embodiment 1:

[0017] Under nitrogen protection, 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 rapidly stirred at 70°C for 12 hours. After the reaction was complete, 20 mL of deionized water was added to the reaction system, and after extraction and separation, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 3.31 g of the product was obtained by column chromatography separation with a yield of 87%.

[0018] The H NMR spectra of methoxy-substituted spiroindole pyrrolidone compounds are as follows Figure 1 Shown, 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). Embodiment 2:

[0019]

[0020] Under nitrogen protection, 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 rapidly stirred at 60°C for 12 hours. After the reaction was complete, 20 mL of deionized water was added to the reaction system, and after extraction and separation, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 3.02 g of the product was obtained by column chromatography separation with a yield of 80%.

[0021] Embodiment 3:

[0022] Under nitrogen protection, 50 mL of dichloroethane, 10 mL of methanol, 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 into a reaction system and rapidly stirred at 70°C for 12 hours. After the reaction was complete, 20 mL of deionized water was added to the reaction system, and after extraction and separation, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 2.57 g of the product was obtained by column chromatography separation with a yield of 68%.

[0023] Embodiment 4:

[0024] Under nitrogen protection, 50 mL of dichloroethane, 10 mL of methanol, substituted indole propionamide (3.48 g, 10 mmol), N-iodosuccinimide (4.95 g, 22 mmol) and sodium carbonate (2.12 g, 20 mmol) were mixed into a reaction system and rapidly stirred at 70°C for 12 hours. After the reaction was complete, 20 mL of deionized water was added to the reaction system, and after extraction and separation, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 3.06 g of the product was obtained by column chromatography separation with a yield of 81%.

[0025] Embodiment 5:

[0026] Under nitrogen protection, 50 mL of chloroform, 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 rapidly stirred at 70°C for 12 hours. After the reaction was complete, 20 mL of deionized water was added to the reaction system, and after extraction and separation, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and 2.95 g of the product was obtained by column chromatography separation with a yield of 78%.

[0027] Bactericidal activity test: Considering the potential biological activity of spiroindole pyrrolidone compounds, we tested the fungicidal activity of the compounds synthesized in Example 1 (Table 1). Common plant fungi include tomato early blight, cucumber gray mold, wheat fusarium, rice blast, pepper phytophthora, rice sheath blight, and rape sclerotia. The experimental results show that the fungicidal activity results of the products (in vitro test (50 μg / mL), inhibition rate ± standard deviation (%)) show that with thiophanate-methyl and carbendazim as comparison agents, spiroindole pyrrolidone compounds show inhibitory activity against the test fungi, especially against tomato early blight, wheat fusarium, pepper phytophthora and rape sclerotia, showing an inhibitory effect comparable to or even better than the comparison agent.

[0028]

[0029] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a methoxyspiroindole pyrrolidone compound, comprising the following: The substituted indole propionamide undergoes dearomatization oxyamination reaction under the action of an oxidant and a base to obtain a methoxy-substituted spiroindole pyrrolidone compound. The synthesized compound has excellent inhibitory activity against specific plant fungi.

2. The method according to claim 1, characterized in that In the synthesis reaction of the methoxy-substituted spiroindole pyrrolidone compound, the temperature is 40-100° C. and the time is 6-20 h.

3. The method according to claim 1, characterized in that In the synthesis reaction of the methoxy-substituted spiroindole pyrrolidone compound, the oxidant is one of NIS (N-iodosuccinimide) and NBS (N-bromosuccinimide).

4. The method according to claim 1, characterized in that In the synthesis reaction of the methoxy-substituted spiroindole pyrrolidone compound, the base comprises one of potassium carbonate, sodium carbonate and cesium carbonate.

5. The method according to claim 1, characterized in that In the synthesis reaction of the methoxy-substituted spiroindole pyrrolidone compound, the solvent is a mixed solvent of chloroform, dichloromethane, DMF (N,N-dimethylformamide) and methanol.

6. The method according to claim 1, characterized in that In the synthesis reaction of the methoxy-substituted spiroindole pyrrolidone compound, the molar ratio of the substituted indole propionamide, the oxidant and the base is 1:(2-2.5):(2-2.5).

7. The method according to claim 1, characterized in that The specific plant fungus is at least one of tomato early blight, cucumber gray mold, wheat gibberella, rice blast, pepper phytophthora, rice sheath blight, and rapeseed sclerotium.

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