A method for the electro-oxidative cyclization synthesis of 1-aminoindole derivatives

Abstract

This invention discloses a method for the electro-oxidative cyclization synthesis of 1-aminoindole derivatives, comprising the following steps: adding an acetylphenylhydrazine derivative, an alkyne derivative, [Cp*RhCl2]2, sodium acetate, potassium hexafluorophosphate, t-BuOH, and distilled water to a container equipped with magnetic electrodes to obtain a mixed reaction solution; placing the mixed reaction solution in a sand bath preheated to a predetermined temperature, using a carbon rod as the anode and a platinum sheet as the cathode, inserting one end of the cathode and anode alternately into the mixed reaction solution, and connecting the other end of the cathode and anode to an electrochemical workstation to construct an electro-oxidative cyclization system; and energizing the electrochemical workstation for a predetermined reaction time to obtain the 1-aminoindole derivative. The method provided by this invention uses flowing electrons as the oxidant instead of an external oxidant, and achieves catalyst regeneration through an internal circulation driven by an electrochemical workstation, eliminating the need for an external oxidant. Its reaction conditions are mild, the synthesis steps are simple, and the reaction time is short.

Description

Technical Field

[0001] This invention relates to the field of organic compound synthesis technology, and in particular to a method for the electro-oxidative cyclization synthesis of 1-aminoindole derivatives. Background Technology

[0002] 1-Aminoindole derivatives are indole aromatic amines, and aromatic amines are important intermediates and starting materials in organic synthesis. 1-Aminoindole derivatives exhibit unique physiological activities in pharmaceuticals and pesticides, and have important applications in the synthesis of antipyretics, analgesics, stimulants, and antispasmodics. In addition, they also have important applications in the synthesis of pesticides, pharmaceuticals, dyes, surfactants, and photosensitive materials. Therefore, the efficient and safe synthesis of 1-aminoindole derivatives is of significant research value.

[0003] Traditional methods for synthesizing 1-aminoindole derivatives mainly include palladium-catalyzed intramolecular cyclization of (2-chlorophenyl)acetaldehyde dimethylhydrazone; palladium-catalyzed o-chlorophenylacetylene and... N,N- Intermolecular condensation reactions of disubstituted hydrazines. However, these methods have many problems, such as 1) the need for amination and low conversion of starting materials; 2) complex synthesis steps; and 3) limited synthesis range.

[0004] To address the aforementioned problems, in 2014, Liu Peinian's research group reported a method for synthesizing 1-aminoindole derivatives via a rhodium-catalyzed oxidative cyclization reaction of acetylphenylhydrazine and alkynes using 1,3-dinitrobenzene as an oxidant. Org.Lett. (2014, 16, 6176). This synthetic method is characterized by high efficiency, few steps, and good atom economy, but this reaction system requires the use of an oxidant. In 2017, Cui Xiuling et al. disclosed the synthesis of 1-aminoindole compounds by condensation reaction of phenylhydrazine hydrochloride derivatives and acyl diazo compounds in the presence of ketone organic compounds and under rhodium catalysis (Chinese Patent CN 107098847A). This synthetic method does not require the addition of an oxidant. However, the diazo compounds used in this method are hazardous and explosive, posing a safety hazard.

[0005] Therefore, existing technologies still need to be improved and developed. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the purpose of this invention is to provide a method for the electro-oxidative cyclization synthesis of 1-aminoindole derivatives, which aims to solve the problems of existing methods for preparing 1-aminoindole derivatives requiring the use of external oxidants or dangerous and explosive diazo compounds, resulting in long reaction times and high energy consumption.

[0007] The technical solution of the present invention is as follows: A method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization, comprising the steps of: Containing acetylphenylhydrazine derivatives, alkyne derivatives, [Cp] RhCl2]2, sodium acetate, potassium hexafluorophosphate, t-BuOH and distilled water are added to a container with a magnetic oscillator to obtain a mixed reaction solution; The mixed reaction solution is placed in a sand bath preheated to a predetermined temperature, with a carbon rod as the anode and a platinum sheet as the cathode. One end of the cathode and the anode are inserted into the mixed reaction solution at intervals, and the other end of the cathode and the anode are connected to an electrochemical workstation to construct an electro-oxidation cyclization system. The electrochemical workstation was energized and reacted for a predetermined time to prepare a 1-aminoindole derivative.

[0008] The method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization, wherein the chemical structural formula of the acetylphenylhydrazine derivative is: R1-R4 are independently selected from hydrogen, halogen, alkyl, methoxy and cyano, and R5 is aryl.

[0009] The method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization, wherein the structural formula of the alkyne derivative is: R6-R7 are independently selected from alkyl and aromatic groups.

[0010] The method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization, wherein the volume ratio of t-BuOH to distilled water in the mixed reaction solution is 1:1.

[0011] The method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization includes placing the mixed reaction solution in a sand bath preheated to a predetermined temperature of 90-110°C.

[0012] In the method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization, the step of energizing the electrochemical workstation for a predetermined reaction time is 2-3 hours.

[0013] The method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization further includes the following step after energizing the electrochemical workstation for a predetermined reaction time: Remove the product solution obtained after the reaction from the sand bath, then add dichloromethane to the product solution and transfer it to a round-bottom flask; The solvent in the round-bottom flask was removed by rotary evaporation, and the product was obtained by passing it through a silica gel column, thus preparing the 1-aminoindole derivative.

[0014] Beneficial effects: This invention constructs an electro-oxidation cyclization system and synergistically uses a catalyst [Cp] RhCl2]2 co-electrocatalyzes the activation of the CH bond of the benzene ring in acetylphenylhydrazine derivatives, which then undergoes a cyclization reaction with readily available and commercially available acetylene derivatives (C2 source) to synthesize 1-aminoindole compounds. The method provided by this invention uses mobile electrons as the oxidant instead of an external oxidant, and achieves catalyst regeneration through an internal circulation driven by an electrochemical workstation. It eliminates the need for an external oxidant, offers mild reaction conditions, simple synthetic steps, and short reaction time, providing an effective and green synthetic route for preparing biologically active 1-aminoindole compounds that can be better modified and derivatized. Attached Figure Description

[0015] Figure 1 This is a flowchart of a method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization according to the present invention.

[0016] Figure 2 This is a schematic diagram illustrating the reaction principle of an electro-oxidative cyclization synthesis of 1-aminoindole derivatives according to the present invention. Detailed Implementation

[0017] To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions of the embodiments of this disclosure will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this disclosure. All other embodiments obtained by those skilled in the art based on the described embodiments of this disclosure without creative effort are within the scope of protection of this invention.

[0018] It should be understood that, without conflict, any and all embodiments of the present invention can be combined with technical features of any other embodiment or multiple other embodiments to obtain other embodiments. The present invention includes such combinations to obtain other embodiments.

[0019] In this specification, groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.

[0020] The chapter headings used in this specification are for organizational purposes only and should not be construed as limiting the subject matter. All references or portions thereof cited in this invention, including but not limited to patents, patent applications, articles, books, user manuals, and papers, are incorporated herein by reference in their entirety.

[0021] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0022] It should be understood that the singular forms used in this invention, such as "a," include plural references unless otherwise specified. Furthermore, the term "comprising" is an open-ended limitation, not a closed one; that is, it includes the contents specified in this invention but does not exclude other aspects.

[0023] Please see Figure 1 , Figure 1 A flowchart of a method for the electro-oxidative cyclization synthesis of 1-aminoindole derivatives provided by the present invention is shown in the figure, which includes the following steps: S10, containing acetylphenylhydrazine derivatives, alkyne derivatives, [Cp] RhCl2]2, sodium acetate, potassium hexafluorophosphate, t-BuOH and distilled water are added to a container with a magnetic oscillator to obtain a mixed reaction solution; S20. Place the mixed reaction solution in a sand bath preheated to a predetermined temperature, with a carbon rod as the anode and a platinum sheet as the cathode. Insert one end of the cathode and the anode into the mixed reaction solution at intervals, and connect the other end of the cathode and the anode to an electrochemical workstation to construct an electro-oxidation cyclization system. S30. The electrochemical workstation is energized and reacted for a predetermined time to obtain a 1-aminoindole derivative.

[0024] Specifically, in traditional CH-activated oxidative cyclization processes, a transition metal catalyst is often required to first oxidize to an active intermediate before combining with the substrate to activate the CH bond. After the reaction, a large amount of oxidized transition metal remains, necessitating the consumption of a large amount of external oxidant to achieve reduction and recovery of the transition metal catalyst. This invention, however, constructs an electro-oxidative cyclization system and synergistically uses the catalyst [Cp] RhCl2]2 co-electrocatalyzes the activation of the CH bond of the benzene ring in acetylphenylhydrazine derivatives, which then undergoes a cyclization reaction with readily available and commercially available acetylene derivatives as C2 sources to synthesize 1-aminoindole compounds. The method provided in this invention uses mobile electrons as the oxidant instead of an external oxidant. The dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer can be regenerated within the system via an electrochemical workstation. This invention eliminates the need for an external oxidant, features mild reaction conditions, simple synthesis steps, and short reaction time, providing an effective and green synthetic route for preparing biologically active 1-aminoindole compounds that can be better modified and derivatized.

[0025] In some embodiments, the chemical structural formula of the acetylphenylhydrazine derivative is as follows: Wherein, R1-R4 are independently selected from one of hydrogen, halogen, alkyl, methoxy, and cyano groups, and R5 is an aryl group; the structural formula of the alkyne derivative is: R6-R7 are independently selected from alkyl and aromatic groups.

[0026] In this embodiment, the acetylphenylhydrazine derivative With alkyne derivatives The reaction process is as follows Figure 2 As shown, the acetylphenylhydrazine derivative in the electro-oxidative cyclization system and with the synergistic catalyst [Cp] Under the co-electrocatalysis of RhCl2, the CH bond on its benzene ring is activated and undergoes a cyclization reaction with an acetylene derivative derived from C2, synthesizing 1-aminoindole compounds. .

[0027] In some embodiments, the volume ratio of t-BuOH to distilled water in the mixed reaction solution is 1:1.

[0028] In some embodiments, the mixed reaction solution is placed in a sand bath preheated to a predetermined temperature of 90-110°C. For example, the predetermined temperature can be 90°C, 95°C, 100°C, 105°C, 110°C, etc., but is not limited to this.

[0029] In some embodiments, the step of energizing the electrochemical workstation for a predetermined reaction time is 2-3 hours. For example, the predetermined time can be 2 hours, 2.5 hours, 3 hours, etc., but is not limited to this.

[0030] In some embodiments, after the electrochemical workstation is powered on and reacted for a predetermined time, the process further includes the following steps: removing the product solution obtained after the reaction from the sand bath, then adding dichloromethane to the product solution and transferring it to a round-bottom flask; removing the solvent in the round-bottom flask using a rotary evaporator, and passing the solution through a silica gel column to obtain the target product, thus preparing the 1-aminoindole derivative.

[0031] The present invention will be further explained and illustrated below through specific embodiments: Example 1 N-(1-acetamido-2,3-diphenyl)-2-neopentole Synthesis method: 1. In a pre-dried 25 mL three-necked flask equipped with a magnetic flask, add 0.6 mmol of 1-neopentaneacetylhydrazine, 0.3 mmol of diphenylacetylene, and 9.6 mg (0.015 mmol, 20%) [Cp] RhCl2]2, 26.3 mg (0.03 mmol) sodium acetate, 55.2 mg (0.3 mmol) potassium hexafluorophosphate, followed by 6.0 mL of a 1:1 mixture of t-BuOH and distilled water; 2. The reaction tube was placed in a preheated 100℃ sand bath, with a carbon rod as the anode and a platinum sheet as the cathode. The reaction was carried out for 2.5 hours using an electrochemical workstation. The reaction was then removed from the heat source, and dichloromethane was added. The mixture was then transferred to a round-bottom flask and the solvent was removed using a rotary evaporator. The product was obtained by passing ethyl acetate / petroleum ether (1:4) through a silica gel column, yielding 57.7 mg of the target product, with a yield of 56%.

[0032] Example 2 N-(1-acetamido-2,3-diphenyl)-1H-indole Synthesis method: 1. In a pre-dried 25 mL three-necked flask equipped with a magnetic flask, add m-methylacetylhydrazine (0.6 mmol), diphenylacetylene (0.3 mmol), and 9.6 mg (0.015 mmol, 20%) [Cp] RhCl2]2, 26.3 mg (0.03 mmol) sodium acetate, 55.2 mg (0.3 mmol) potassium hexafluorophosphate, followed by 6.0 mL of a 1:1 mixture of t-BuOH and distilled water; 2. The reaction tube was placed in a preheated 90℃ sand bath with a carbon rod as the anode and a platinum sheet as the cathode. The reaction was connected to an electrochemical workstation and powered on for 3 hours. The reaction was then removed from the heat source, and dichloromethane was added. The mixture was then transferred to a round-bottom flask and the solvent was removed by a rotary evaporator. Ethyl acetate / petroleum ether = 1:4 was passed through a silica gel column to obtain 49.8 mg of the target product, with a yield of 48%.

[0033] Example 3 N-(1-acetamido-2-cyclopropane)-1H-indole Synthesis method: 1. In a pre-dried 25 mL three-necked flask equipped with a magnetic flask, add acetylphenylhydrazine (0.6 mmol), cyclopropanethylene (0.3 mmol), and 9.6 mg (0.015 mmol, 20%) [Cp] RhCl2]2, 26.3 mg (0.03 mmol) sodium acetate, 55.2 mg (0.3 mmol) potassium hexafluorophosphate, followed by 6.0 mL of a 1:1 mixture of t-BuOH and distilled water; 2. The reaction tube was placed in a preheated sand bath at 110°C, with a carbon rod as the anode and a platinum sheet as the cathode. The reaction was carried out for 2 hours using an electrochemical workstation. The reaction was then removed from the heat source, and dichloromethane was added. The mixture was then transferred to a round-bottom flask and the solvent was removed using a rotary evaporator. The product was obtained by passing ethyl acetate / petroleum ether at a ratio of 1:4 through a silica gel column, yielding 28 mg of the target product, with a yield of 43%.

[0034] Example 4 N-(1-acetamido-2-m-methylbenzene)-1H-indole Synthesis method: 1. In a pre-dried 25 mL three-necked flask equipped with a magnetic flask, add acetylphenylhydrazine (0.6 mmol), 3-ethynyltoluene (0.3 mmol), and 9.6 mg (0.015 mmol, 20%) [Cp] RhCl2]2, 26.3 mg (0.03 mmol) sodium acetate, 55.2 mg (0.3 mmol) potassium hexafluorophosphate, followed by 6.0 mL of a 1:1 mixture of t-BuOH and distilled water; 2. The reaction tube was placed in a preheated 100℃ sand bath with a carbon rod as the anode and a platinum sheet as the cathode. The reaction was carried out for 2.5 hours by connecting an electrochemical workstation. The reaction was then removed from the heat source, and dichloromethane was added. The mixture was then transferred to a round-bottom flask and the solvent was removed by a rotary evaporator. The product was obtained by passing ethyl acetate / petroleum ether in a ratio of 1:4 through a silica gel column, yielding 28 mg of the target product, with a yield of 26%.

[0035] It should be understood that the application of the present invention is not limited to the examples above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.

Claims

1. A method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization, characterized in that, Including the following steps: Containing acetylphenylhydrazine derivatives, alkyne derivatives, [Cp] RhCl2]2, sodium acetate, potassium hexafluorophosphate, t-BuOH and distilled water are added to a container containing a magnetic oscillator to obtain a mixed reaction solution; The mixed reaction solution is placed in a sand bath preheated to a predetermined temperature, with a carbon rod as the anode and a platinum sheet as the cathode. One end of the cathode and the anode are inserted into the mixed reaction solution at intervals, and the other end of the cathode and the anode are connected to an electrochemical workstation to construct an electro-oxidation cyclization system. The electrochemical workstation was energized for a predetermined reaction time to prepare a 1-aminoindole derivative; when the acetylphenylhydrazine derivative was 1-neopentylacetylhydrazine and the alkyne derivative was diphenylacetylene, the obtained 1-aminoindole derivative was... When the acetylphenylhydrazine derivative is m-methylacetylphenylhydrazine and the alkyne derivative is diphenylacetylene, the obtained 1-aminoindole derivative is When the acetylphenylhydrazine derivative is acetylphenylhydrazine and the alkyne derivative is cyclopropylacetylene, the obtained 1-aminoindole derivative is... When the acetylphenylhydrazine derivative is acetylphenylhydrazine and the alkyne derivative is 3-ethynyltoluene, the obtained 1-aminoindole derivative is... .

2. The method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization according to claim 1, characterized in that, In the mixed reaction solution, the volume ratio of t-BuOH to distilled water is 1:

1.

3. The method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization according to claim 1, characterized in that, The mixed reaction solution is placed in a sand bath preheated to a predetermined temperature of 90-110°C.

4. The method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization according to claim 1, characterized in that, In the step of energizing the electrochemical workstation for a predetermined reaction time, the predetermined time is 2-3 hours.

5. The method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization according to claim 1, characterized in that, After the electrochemical workstation is energized and reacted for a predetermined time, the process further includes the following steps: Remove the product solution obtained after the reaction from the sand bath, then add dichloromethane to the product solution and transfer it to a round-bottom flask; The solvent in the round-bottom flask was removed by rotary evaporation, and the product was obtained by passing it through a silica gel column, thus preparing the 1-aminoindole derivative.

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