One-step electrochemical synthesis method of spiro pyrrolidinyl oxindole compounds

Abstract

The present invention discloses a one-step electrochemical synthesis method of a spiro pyrrolidinyl oxindole compound, which is directly prepared by a one-step electrochemical reaction method. The preparation route is as follows: #imgabs0# wherein, R 1 is any one of hydrogen or alkyl; R 2 is a mono-substituted or multi-substituted group; R 3 is any one of hydrogen or alkyl; R 4 is any one of a sulfonyl group, a tert-butoxycarbonyl group or alkyl; R 5 is any one of hydrogen or alkyl; R 6 is any one of hydrogen, alkyl or alkoxy; R 7 is any one of hydrogen, alkyl or alkoxy; M is a metal ion. Under electrochemical conditions, the present invention obtains a spiro pyrrolidinyl oxindole compound in one step. The synthesis route is short, the reaction operation is simple and easy to control, the conditions are mild, the yield is excellent, no expensive catalyst is required, the cost is low, and the efficiency is high.

Description

Technical Field

[0001] The present invention relates to a one-step electrochemical synthesis method of spiro-pyrrolidinyl oxindole compounds, belonging to the technical field of the synthesis of spiro-pyrrolidinyl oxindole compounds. Background Art

[0002] The spiro-pyrrolidinyl oxindole skeleton widely exists in natural products and drug molecules and is the core structural unit of a variety of bioactive compounds, such as coerulescine, horsfiline, elacomine, strychnofoline, alkaloid BACE1 inhibitor, etc.

[0003]

[0004] Due to their important biological activities, spiro-pyrrolidinyl oxindole compounds have always been a research hotspot in the field of organic synthesis. However, their structures are complex and the synthesis is difficult. There are also few reported synthesis methods at present, and most of them are multi-step reactions or require special expensive catalysts, with great limitations. For example, in 2018, Professor Eelco Ruijter developed a two-step reaction method using 3-isocyanoethyl oxindole as the starting material, first through addition with N-iodosuccinimide and then reduction with ammonia borane to synthesize spiro-pyrrolidinyl oxindole compounds, with a yield of about 60%. The present invention proposes a more green and simple synthesis route, and spiro-pyrrolidinyl oxindole compounds are prepared through a one-step reaction under electrochemical conditions. Summary of the Invention

[0005] The present invention provides a synthesis method for preparing spiro-pyrrolidinyl oxindole compounds under electrochemical conditions. Using 3-aminomethyl-substituted indole containing an unsaturated bond as a raw material, spiro-pyrrolidinyl oxindole compounds are synthesized in one step under electrochemical conditions with tetrabutylammonium iodide and trifluoromethylsulfonate. The reaction operation is simple, the conditions are mild, the yield is excellent, no expensive catalyst is required, the cost is low, the efficiency is high, and it conforms to the chemical concept of green synthesis.

[0006] To solve the above technical problems, the technical solutions adopted by the present invention are as follows:

[0007] A one-step electrochemical synthesis method of spiro-pyrrolidinyl oxindole compounds is directly prepared by a one-step electrochemical reaction method. The preparation route is as follows:

[0008]

[0009] Among them, R

[0006] , 2 , ,

[0008] ,

[0007] , ,

[0009] , 1 , , , is any one of hydrogen or alkyl; R 2 is a monosubstituted or polysubstituted group; R3 is any one of hydrogen or alkyl; R 4 is any one of sulfonyl, tert-butoxycarbonyl or alkyl; R 5 is any one of hydrogen or alkyl; R 6 is any one of hydrogen, alkyl or alkoxy; R 7 is any one of hydrogen, alkyl or alkoxy; M is a metal ion; the solvent is a mixed solvent of an organic solvent and water.

[0010] To improve the yield, the acid is any one of acetic acid, benzoic acid, trifluoroacetic acid or trifluoromethanesulfonic acid, preferably benzoic acid.

[0011] The organic solvent is preferably any one of acetonitrile, tetrahydrofuran, chlorobenzene, 1,4-dioxane, N,N-dimethylformamide or dimethyl sulfoxide, and further preferably acetonitrile.

[0012] To improve the yield, the volume ratio of the organic solvent to water is 2:1 to 1:2, preferably 2:1.

[0013] The above M is any one of sodium ion, potassium ion or zinc ion; R 2 is any one of alkyl, alkoxy, halogen or aryl.

[0014] As one specific implementation scheme, the one-step electrochemical synthesis method of the spiro pyrrolidinyl oxindole compound is to dissolve 3-aminomethyl-substituted indole containing an unsaturated bond, tetrabutylammonium iodide, trifluoromethylsulfite and an acid in a solvent, insert an electrode into the system, energize and stir the reaction. After the reaction is completed, extract with a solvent, then remove the solvent to obtain a crude product, and finally separate and purify by column chromatography to obtain the target spiro pyrrolidinyl oxindole compound.

[0015] The above column chromatography uses petroleum ether and ethyl acetate with a volume ratio of 3:1 as the eluent.

[0016] To improve the product yield and reduce losses, the molar ratio of 3-aminomethyl-substituted indole containing an unsaturated bond, tetrabutylammonium iodide, trifluoromethylsulfite and an acid is 1:(1 - 3):(1 - 2):(1 - 5), preferably 1:2:1:4.

[0017] The reaction conditions after inserting the electrode are: the current magnitude is 4 - 20 mA, preferably 10 ± 2 mA, the reaction temperature is 25 - 100 °C, preferably 80 ± 5 °C, and the reaction time is 5 - 12 h, preferably 10 ± 0.5 h.

[0018] The electrode in this application is any one of a carbon electrode, a platinum electrode, a copper electrode, a zinc electrode, an iron electrode or a stainless steel electrode.

[0019] For technologies not mentioned in the present invention, reference is made to the prior art.

[0020] The electrochemical synthesis method of the pyrrolidinyl oxindole compound of the present invention uses 3-aminomethyl-substituted indole containing an unsaturated bond as a raw material, and reacts with tetrabutylammonium iodide and trifluoromethylsulfonate under electrochemical conditions to obtain a spiro pyrrolidinyl oxindole compound in one step. The synthesis route is short, the reaction operation is simple and easy to control, the conditions are mild, the yield is excellent, no expensive catalyst is required, the cost is low, and the efficiency is high. Description of the Drawings

[0021] Figure 1 1H NMR spectrum of the target product obtained in Example 1 ( 1 H NMR, 400 MHz, CDCl3);

[0022] Figure 2 13C NMR spectrum of the target product obtained in Example 1 ( 13 C NMR, 150 MHz, CDCl3);

[0023] Figure 3 1H NMR spectrum of the target product obtained in Example 5 ( 1 H NMR, 400 MHz, CDCl3);

[0024] Figure 4 13C NMR spectrum of the target product obtained in Example 5 ( 13 C NMR, 150 MHz, CDCl3);

[0025] Figure 5 1H NMR spectrum of the target product obtained in Example 6 ( 1 H NMR, 400 MHz, CDCl3);

[0026] Figure 6 13C NMR spectrum of the target product obtained in Example 6 ( 13 C NMR, 150 MHz, CDCl3);

[0027] Figure 7 1H NMR spectrum of the target product obtained in Example 7 ( 1 H NMR, 400 MHz, CDCl3);

[0028] Figure 8 13C NMR spectrum of the target product obtained in Example 7 ( 13 C NMR, 150 MHz, CDCl3); Detailed Description of the Invention

[0029] To better understand the present invention, the content of the present invention will be further clarified below in conjunction with embodiments. However, the content of the present invention is not limited to the following embodiments only.

[0030] In each example, the preparation of 3-aminomethyl-substituted indoles containing unsaturated bonds was referred to: Visible-Light-Irradiated Cascade Reaction of Indole-Tethered Alkenes to Access Tetracyclic Tetrahydro-γ-carbolines. Organc Letters, 2022, 24, 2630-2635.

[0031] Example 1

[0032] Weigh 0.2 mmol of 3-aminomethyl-substituted indoles containing unsaturated bonds (R 1 =R 2 =R 3 =R 5 =R 6 =R 7 =H, R 4 =Ts (p-toluenesulfonyl)), 0.2 mmol of sodium trifluoromethanesulfinate, 0.8 mmol of benzoic acid, and 0.4 mmol of tetrabutylammonium iodide were dissolved in a mixed solution of 6 mL of acetonitrile and 3 mL of water. A carbon sheet (10 mm×10 mm×0.2 mm) electrode was inserted into the solution as the positive electrode, and a platinum metal sheet (10 mm×10 mm×0.2 mm) electrode was used as the negative electrode. After connecting the power supply, the current was controlled to be constant at 10 mA, and the mixture was stirred at 80 °C for 10 hours. After the reaction was completed, 30 mL of ethyl acetate and 30 mL of water were added. After liquid separation, the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. Then, column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, with a volume ratio of 3:1) was used for separation and purification to obtain the target product. The proton nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum are as Figure 1-2 shown, with a yield of 96% and a purity > 99.9%.

[0033] Comparative Example 1

[0034] Replace 6 mL of acetonitrile in Example 1 with 6 mL of water, that is, a total of 9 mL of water. The rest was the same as in Example 1. The yield was 9%, which was meaningless for production and was regarded as a failure.

[0035] Example 2

[0036] Weigh 0.2 mmol of 3-aminomethyl-substituted indoles containing unsaturated bonds (R 1 =R 2 =R 3 =R 5= R 6 = R 7 = H, R 4 = Ts), 0.2 mmol of sodium trifluoromethanesulfinate, 0.8 mmol of acetic acid and 0.4 mmol of tetrabutylammonium iodide were dissolved in a mixed solution of 6 mL of dioxane and 3 mL of water. Carbon plates (10 mm × 10 mm × 0.2 mm) were inserted into the solution as the positive electrode, and a metal platinum plate (10 mm × 10 mm × 0.2 mm) was used as the negative electrode. After connecting the power supply, the current was controlled to be constant at 10 mA, and the heating system was stirred at 80 °C for 10 hours. After the reaction was completed, 30 mL of ethyl acetate and 30 mL of water were added. After stratification, the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. Then, column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio 3:1) was used for separation and purification to obtain the target product. The 1H NMR spectrum and 13C NMR spectrum were not substantially different from those in Example 1 and are not provided again. The yield was 76%, and the purity was >99.9%.

[0037] Example 3

[0038] 0.2 mmol of 3-aminomethyl-substituted indole containing an unsaturated bond (R 1 = R 2 = R 3 = R 5 = R 6 = R 7 = H, R 4 = Ts), 0.2 mmol of sodium trifluoromethanesulfinate, 0.8 mmol of acetic acid and 0.4 mmol of tetrabutylammonium iodide were dissolved in a mixed solution of 6 mL of acetonitrile and 3 mL of water. Carbon plates (10 mm × 10 mm × 0.2 mm) were inserted into the solution as the positive electrode, and a metal platinum plate (10 mm × 10 mm × 0.2 mm) was used as the negative electrode. After connecting the power supply, the current was controlled to be constant at 10 mA, and the heating system was stirred at 40 °C for 10 hours. After the reaction was completed, 30 mL of ethyl acetate and 30 mL of water were added. After stratification, the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. Then, column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio 3:1) was used for separation and purification to obtain the target product. The 1H NMR spectrum and 13C NMR spectrum were not substantially different from those in Example 1 and are not provided again. The yield was 63%, and the purity was >99.9%.

[0039] Example 4

[0040] 0.2 mmol of 3-aminomethyl-substituted indole containing an unsaturated bond (R 1 = R 2 = R 3 = R 5 = R6 = R 7 = H, R 4 = Ts), 0.2 mmol of sodium trifluoromethanesulfinate, 0.8 mmol of acetic acid and 0.4 mmol of tetrabutylammonium iodide were dissolved in a mixed solution of 6 mL of acetonitrile and 3 mL of water. Carbon sheet (10 mm × 10 mm × 0.2 mm) electrodes were inserted into the solution as the positive electrode, and metal platinum sheet (10 mm × 10 mm × 0.2 mm) electrodes were used as the negative electrode. After connecting the power supply, the current was controlled to be constant at 10 mA, and the mixture was stirred at 80 °C for 10 hours. After the reaction was completed, 30 mL of ethyl acetate and 30 mL of water were added. After phase separation, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. Then, column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio 3:1) was used for separation and purification to obtain the target product. The 1H NMR spectrum and 13C NMR spectrum were not substantially different from those in Example 1 and are not provided again. The yield was 79%, and the purity > 99.9%.

[0041] Example 5

[0042] Weighed 0.2 mmol of 3-aminomethyl-substituted indole containing an unsaturated bond (R 1 = R 3 = R 4 = R 5 = R 6 = R 7 = H, R 2 = 3-Br, R 4 = Ts), 0.2 mmol of sodium trifluoromethanesulfinate, 0.8 mmol of benzoic acid and 0.4 mmol of tetrabutylammonium iodide were dissolved in a mixed solution of 6 mL of acetonitrile and 3 mL of water. Carbon sheet (10 mm × 10 mm × 0.2 mm) electrodes were inserted into the solution as the positive electrode, and metal platinum sheet (10 mm × 10 mm × 0.2 mm) electrodes were used as the negative electrode. After connecting the power supply, the current was controlled to be constant at 10 mA, and the mixture was stirred at 80 °C for 10 hours. After the reaction was completed, 30 mL of ethyl acetate and 30 mL of water were added. After phase separation, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. Then, column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio 3:1) was used for separation and purification to obtain the target product. The 1H NMR spectrum and 13C NMR spectrum are as Figure 3-4 shown. The yield was 84%, and the purity > 99.9%.

[0043] Example 6

[0044] Weighed 0.2 mmol of 3-aminomethyl-substituted indole containing an unsaturated bond (R 1 = R 3 = R 4 = R 5= R 6 = R 7 = H, R 2 = 3-CH3, R 4 = Ts), 0.2 mmol of sodium trifluoromethanesulfinate, 0.8 mmol of benzoic acid and 0.4 mmol of tetrabutylammonium iodide were dissolved in a mixed solution of 6 mL of acetonitrile and 3 mL of water. A carbon sheet (10 mm × 10 mm × 0.2 mm) electrode was inserted into the solution as the positive electrode, and a metal platinum sheet (10 mm × 10 mm × 0.2 mm) electrode was used as the negative electrode. After connecting the power supply, the current was controlled to be constant at 10 mA, and the mixture was stirred at 80 °C for 10 hours. After the reaction was completed, 30 mL of ethyl acetate and 30 mL of water were added. After liquid separation, the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. Then, column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio 3:1) was used for separation and purification to obtain the target product. The 1H NMR spectrum and 13C NMR spectrum are as Figure 5-6 shown, the yield was 88%, and the purity > 99.9%.

[0045] Example 7

[0046] Weighed 0.2 mmol of 3-aminomethyl-substituted indole containing an unsaturated bond (R 1 = R 2 = R 3 = R 5 = R 6 = R 7 = H, R 4 = Bs (p-bromobenzenesulfonyl)), 0.2 mmol of sodium trifluoromethanesulfinate, 0.8 mmol of benzoic acid and 0.4 mmol of tetrabutylammonium iodide were dissolved in a mixed solution of 6 mL of acetonitrile and 3 mL of water. A carbon sheet (10 mm × 10 mm × 0.2 mm) electrode was inserted into the solution as the positive electrode, and a metal platinum sheet (10 mm × 10 mm × 0.2 mm) electrode was used as the negative electrode. After connecting the power supply, the current was controlled to be constant at 10 mA, and the mixture was stirred at 80 °C for 10 hours. After the reaction was completed, 30 mL of ethyl acetate and 30 mL of water were added. After liquid separation, the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. Then, column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio 3:1) was used for separation and purification to obtain the target product. The 1H NMR spectrum and 13C NMR spectrum are as Figure 7-8 shown, the yield was 82%, and the purity > 99.9%.

Claims

1. One-step electrochemical synthesis method of spiro pyrrolidinyl oxindole compound, characterized in that: It is directly prepared by a one-step electrochemical reaction method, and the preparation route is as follows: Among them, R 1 is any one of hydrogen or alkyl; R 2 is any one of hydrogen, alkyl, alkoxy, halogen or aryl; R 3 is any one of hydrogen or alkyl; R 4 is p-toluenesulfonyl or p-bromobenzenesulfonyl; R 5 is any one of hydrogen or alkyl; R 6 is any one of hydrogen, alkyl or alkoxy; R 7 is any one of hydrogen, alkyl or alkoxy; M is a metal ion; the solvent is a mixed solvent of an organic solvent and water; The acid is any one of acetic acid, benzoic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; The organic solvent is any one of acetonitrile, tetrahydrofuran, chlorobenzene, 1,4-dioxane, N,N-dimethylformamide or dimethyl sulfoxide; The volume ratio of the organic solvent to water is 2:1 to 1:2; M is any one of sodium, potassium or zinc.

2. The one-step electrochemical synthesis method of the spiro pyrrolidinyl oxindole compound as described in claim 1, characterized in that: 3-Aminomethyl-substituted indole containing an unsaturated bond, tetrabutylammonium iodide, trifluoromethylsulfinate and an acid are dissolved in a solvent, an electrode is inserted into the system, electric current is applied and stirring reaction is carried out. After the reaction is completed, extraction is carried out with a solvent, and then the solvent is removed to obtain a crude product. Finally, purification is carried out by column chromatography to obtain the target spiro pyrrolidinyl oxindole compound.

3. The one-step electrochemical synthesis method of the spiro pyrrolidinyl oxindole compound according to claim 2, characterized in that: The molar ratio of 3-aminomethyl-substituted indole containing an unsaturated bond, tetrabutylammonium iodide, trifluoromethylsulfinate and an acid is 1:(1-3):(1-2):(1-5).

4. The one-step electrochemical synthesis method of the spiro pyrrolidinyl oxindole compound according to claim 2 or 3, characterized in that: Reaction conditions: the magnitude of the electric current is 4-20 mA, the reaction temperature is 25-100 °C, and the reaction time is 5-12 h.

5. The one-step electrochemical synthesis method of the spiro pyrrolidinyl oxindole compound according to claim 2 or 3, characterized in that: The electrode is any one of a carbon electrode, a platinum electrode, a copper electrode, a zinc electrode, an iron electrode or a stainless steel electrode.

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