Method for synthesizing 1-aminoindole derivative through electrooxidation cyclization

Abstract

The invention discloses a method for synthesizing a 1-aminoindole derivative through electrooxidation cyclization, which comprises the following steps: adding an acetyl phenylhydrazine derivative, an alkyne derivative, [Cp * RhCl2] 2, sodium acetate, potassium hexafluorophosphate, t-BuOH and distilled water into a container filled with magnetons to obtain a mixed reaction solution; placing the mixed reaction liquid in a sand bath preheated to a preset temperature, taking a carbon rod as an anode and a platinum sheet as a cathode, inserting one ends of the cathode and the anode into the mixed reaction liquid at intervals, and connecting the other ends of the cathode and the anode to an electrochemical workstation to construct an electrooxidation cyclization system; and electrifying the electrochemical workstation to react for a preset time, so as to prepare the 1-aminoindole derivative. The method provided by the invention takes flowing electrons as an oxidant to replace an external oxidant, realizes regeneration internal circulation of the catalyst through driving of an electrochemical workstation, does not need the external oxidant, and is mild in reaction condition, simple in synthesis step and relatively short in reaction time.

Description

Technical Field

[0001] The invention relates to the technical field of organic compound synthesis, and in particular to a method for synthesizing 1-aminoindole derivatives by electro-oxidation cyclization. Background Art

[0002] 1-Aminoindole derivatives are indole aromatic amines, and aromatic amine compounds are important organic synthesis intermediates and raw materials. 1-Aminoindole derivatives show unique physiological activities in medicine and pesticides, and have important applications in the synthesis of antipyretic analgesics, stimulants, spasmolytics and other drugs. In addition, it also has important applications in the synthesis of pesticides, medicines, dyes, surfactants, photosensitive materials, etc. Therefore, how to efficiently and safely synthesize 1-aminoindole derivatives is of great research value.

[0003] Traditional methods for synthesizing 1-aminoindole derivatives mainly include palladium-catalyzed intramolecular cyclization of (2-chlorophenyl)acetaldehyde dimethylhydrazone and palladium-catalyzed intermolecular condensation reaction of o-chlorophenylacetylene and N,N-disubstituted hydrazine. However, these methods have many problems, such as 1) amination is required, and the conversion rate of starting materials is low; 2) the synthesis steps are complicated; 3) the synthesis range is limited.

[0004] In response to the above problems, in 2014, Liu Peinian's research group reported that 1,3-dinitrobenzene was used as an oxidant to achieve the synthesis of 1-aminoindole derivatives by rhodium-catalyzed oxidative cyclization of acetylphenylhydrazine and alkynes (Org. Lett., 2014, 16, 6176). This synthesis method has the characteristics of 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 hydrochloric acid phenylhydrazine derivatives and acyldiazo compounds in the presence of ketone organic matter and under rhodium catalysis (Chinese patent CN 107098847A). This synthesis method does not require the addition of an oxidant. However, the diazo compound required by this method is dangerous and explosive, and is unsafe.

[0005] Therefore, the prior art still needs to be improved and developed. Summary of the invention

[0006] In view of the above-mentioned deficiencies in the prior art, the purpose of the present invention is to provide a method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization, aiming to solve the problem that the existing preparation methods of 1-aminoindole derivatives require the use of external oxidants or dangerous and explosive diazo compounds, which have long reaction times and high energy consumption.

[0007] The technical solution of the present invention is as follows:

[0008] A method for synthesizing 1-aminoindole derivatives by electro-oxidation cyclization, comprising the steps of:

[0009] The acetylphenylhydrazine derivatives, alkyne derivatives, [Cp*RhCl 2 ] 2 , sodium acetate, potassium hexafluorophosphate, t-BuOH and distilled water are added into a container equipped with a magnetic particle to obtain a mixed reaction solution;

[0010] The mixed reaction liquid is placed in a sand bath preheated to a predetermined temperature, a carbon rod is used as an anode, a platinum sheet is used as a cathode, one end of the cathode and the anode are inserted into the mixed reaction liquid at intervals, and the other ends of the cathode and the anode are connected to an electrochemical workstation to construct an electro-oxidation cyclization system;

[0011] The electrochemical workstation is powered on for a predetermined reaction time to obtain a 1-aminoindole derivative.

[0012] The method for synthesizing 1-aminoindole derivatives by electro-oxidation cyclization, wherein the chemical structural formula of the acetophenylhydrazine derivative is: Among them, R 1 -R 4 is independently selected from one of hydrogen, halogen, alkyl, methoxy and cyano, R 5 It is an aromatic group.

[0013] The method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization, wherein the structural formula of the alkyne derivative is: Among them, R 6 -R 7 Independently selected from one of an alkyl group and an aromatic group.

[0014] The method for synthesizing 1-aminoindole derivatives by electro-oxidation cyclization, wherein the volume ratio of t-BuOH to distilled water in the mixed reaction liquid is 1:1.

[0015] The method for synthesizing 1-aminoindole derivatives by electro-oxidation cyclization comprises placing the mixed reaction solution in a sand bath preheated to a predetermined temperature, wherein the predetermined temperature is 90-110°C.

[0016] The method for synthesizing 1-aminoindole derivatives by electro-oxidation cyclization comprises the following steps: in the step of energizing the electrochemical workstation for a predetermined reaction time, the predetermined time is 2-3 hours.

[0017] The method for synthesizing 1-aminoindole derivatives by electro-oxidation cyclization, wherein, after the electrochemical workstation is powered on for a predetermined reaction time, further comprises the steps of:

[0018] The product solution obtained after the reaction was removed from the sand bath, and then dichloromethane was added to the product solution and transferred to a round-bottom flask;

[0019] The solvent in the round-bottom flask is removed by a rotary evaporator, and the target product is obtained by passing the mixture through a silica gel column, that is, a 1-aminoindole derivative is prepared.

[0020] Beneficial effect: The present invention constructs an electro-oxidation cyclization system and cooperates with the catalyst [Cp*RhCl 2 ] 2 The CH bond of the benzene ring of the acetylphenylhydrazine derivative is activated by co-electrocatalysis, and the 1-aminoindole compound is synthesized by a cyclization reaction with a safe and readily available commercial acetylene derivative as a C2 source. The method provided by the present invention uses mobile electrons as an oxidant to replace an external oxidant, and realizes the internal cycle of catalyst regeneration through an electrochemical workstation drive, without the need for an external oxidant. The reaction conditions are mild, the synthesis steps are simple, and the reaction time is short, providing an effective green synthesis route for the preparation of 1-aminoindole compounds that have biological activity and can be better modified and derivatized. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The present invention is a flow chart of a method for synthesizing 1-aminoindole derivatives by electro-oxidation cyclization.

[0022] Figure 2 The present invention is a reaction principle diagram of the electro-oxidative cyclization synthesis of 1-aminoindole derivatives. DETAILED DESCRIPTION

[0023] In order to make the purpose, technical solution and advantages of the embodiments of the present disclosure clearer, the technical solution of the embodiments of the present disclosure will be clearly and completely described below in conjunction with the drawings of the embodiments of the present disclosure. Obviously, the described embodiments are part of the embodiments of the present disclosure, not all of the embodiments. Based on the described embodiments of the present disclosure, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0024] It should be understood that, under the premise of no conflict, any and all embodiments of the present invention can be combined with the technical features in any other embodiment or multiple other embodiments to obtain another embodiment. The present invention includes such a combination to obtain another embodiment.

[0025] In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds. When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left.

[0026] The section headings used in this specification are only for the purpose of organizing the article and should not be interpreted as limiting the subject matter described. All documents or portions of documents cited in this invention, including but not limited to patents, patent applications, articles, books, manuals and papers, are incorporated herein by reference in their entirety.

[0027] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0028] It should be understood that the singular forms used in the present invention, such as "a", include plural references unless otherwise specified. In addition, the term "comprising" is an open limitation and not a closed one, that is, including the contents specified in the present invention, but not excluding other aspects.

[0029] See also Figure 1 , Figure 1 The present invention provides a flow chart of a method for synthesizing 1-aminoindole derivatives by electro-oxidation cyclization, as shown in the figure, which comprises the steps of:

[0030] S10, with acetylphenylhydrazine derivatives, alkyne derivatives, [Cp*RhCl 2 ] 2 , sodium acetate, potassium hexafluorophosphate, t-BuOH and distilled water are added into a container equipped with a magnetic particle to obtain a mixed reaction solution;

[0031] S20, placing the mixed reaction liquid in a sand bath preheated to a predetermined temperature, using a carbon rod as an anode and a platinum sheet as a cathode, inserting one end of the cathode and the anode into the mixed reaction liquid at intervals, and connecting the other ends of the cathode and the anode to an electrochemical workstation to construct an electro-oxidation cyclization system;

[0032] S30, energizing the electrochemical workstation for a predetermined reaction time to obtain a 1-aminoindole derivative.

[0033] Specifically, in the traditional CH activation oxidation cyclization process, the transition metal catalyst is often required to be oxidized to an active intermediate first, and then combined with the substrate to activate the CH bond. After the reaction is completed, a large amount of oxidized transition metal remains. At this time, a large amount of external oxidant is required to achieve reduction and elimination to recover the transition metal catalyst. The present invention constructs an electro-oxidation cyclization system and cooperates with the catalyst [Cp*RhCl 2 ] 2The CH bond of the benzene ring of the acetylphenylhydrazine derivative is activated by co-electrocatalysis, and the 1-aminoindole compound is synthesized by a cyclization reaction with a safe and readily available commercial acetylene derivative as a C2 source. The method provided by the present invention uses mobile electrons as an oxidant to replace an external oxidant, and the dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer is driven by an electrochemical workstation to achieve regeneration in the system. The present invention does not require an external oxidant, has mild reaction conditions, simple synthesis steps, and a short reaction time, and provides an effective green synthesis route for preparing 1-aminoindole compounds that have biological activity and can be better modified and derivatized.

[0034] In some embodiments, the chemical structural formula of the acetophenylhydrazine derivative is: Among them, R 1 -R 4 is independently selected from one of hydrogen, halogen, alkyl, methoxy and cyano, R 5 is an aryl group; the structural formula of the alkyne derivative is: Among them, R 6 -R 7 Independently selected from one of an alkyl group and an aromatic group.

[0035] In this embodiment, the acetylphenylhydrazine derivative With alkyne derivatives The reaction process is as follows Figure 2 As shown, the acetylphenylhydrazine derivative is in an electrooxidative cyclization system and cooperates with the catalyst [Cp*RhCl 2 ] 2 Under the joint electrocatalysis of , the CH bond on the benzene ring is activated and undergoes a cyclization reaction with the acetylene derivative as the C2 source to synthesize 1-aminoindole compounds.

[0036] In some embodiments, in the mixed reaction liquid, the volume ratio of t-BuOH to distilled water is 1:1. In this embodiment, t-BuOH is sodium triphenylmethane.

[0037] In some embodiments, the mixed reaction liquid is placed in a sand bath preheated to a predetermined temperature, the predetermined temperature is 90-110°C, for example, the predetermined temperature may be 90°C, 95°C, 100°C, 105°C, 110°C, etc., but is not limited thereto.

[0038] In some embodiments, in the step of energizing the electrochemical workstation for a predetermined reaction time, the predetermined time is 2-3 hours. For example, the predetermined time may be 2 hours, 2.5 hours, 3 hours, etc., but is not limited thereto.

[0039] In some embodiments, after the electrochemical workstation is powered on for a predetermined reaction time, the method further comprises 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 by a rotary evaporator, and passing the solution through a silica gel column to obtain the target product, i.e., obtaining a 1-aminoindole derivative.

[0040] The present invention will be further explained below by means of specific embodiments:

[0041] Example 1

[0042] N-(1-Acetamido-2,3-diphenyl)-2-neopentanindole Synthesis method:

[0043] 1. In a pre-dried 25 mL three-necked flask equipped with a magnetic pole, add 1-neopentaneacetylphenylhydrazine (0.6 mmol), diphenylacetylene (0.3 mmol), 9.6 mg (0.015 mmol, 20%) [Cp*RhCl 2 ] 2 , 26.3 mg (0.03 mmol) sodium acetate, 55.2 mg (0.3 mmol) potassium hexafluorophosphate, and then 6.0 mL of a 1:1 mixture of t-BuOH and distilled water;

[0044] 2. Place the reaction tube in a preheated 100°C sand bath, use a carbon rod as the anode and a platinum sheet as the cathode, connect the electrochemical workstation and energize the reaction for 2.5 hours, remove the reaction from the heat source, then add dichloromethane, transfer to a round-bottom flask, use a rotary evaporator to remove the solvent, and pass ethyl acetate / petroleum ether = 1:4 through a silica gel column to obtain 57.7 mg of the target product with a yield of 56%.

[0045] Example 2

[0046] N-(1-Acetamido-2,3-diphenyl)-1H-indole Synthesis method:

[0047] 1. In a pre-dried 25 mL three-necked flask equipped with a magnetic pole, add m-methylacetophenylhydrazine (0.6 mmol), diphenylacetylene (0.3 mmol), 9.6 mg (0.015 mmol, 20%) [Cp*RhCl 2 ] 2 , 26.3 mg (0.03 mmol) sodium acetate, 55.2 mg (0.3 mmol) potassium hexafluorophosphate, and then 6.0 mL of a 1:1 mixture of t-BuOH and distilled water;

[0048] 2. Place the reaction tube in a preheated 90°C sand bath, use a carbon rod as the anode and a platinum sheet as the cathode, connect the electrochemical workstation and power on for 3 hours, remove the reaction from the heat source, then add dichloromethane, transfer to a round-bottom flask, use a rotary evaporator to remove the solvent, and pass ethyl acetate / petroleum ether = 1:4 through a silica gel column to obtain 49.8 mg of the target product with a yield of 48%.

[0049] Example 3

[0050] N-(1-Acetamido-2-cyclopropane)-1H-indole Synthesis method:

[0051] 1. In a pre-dried 25 mL three-necked flask equipped with a magnetic pole, add acetophenylhydrazine (0.6 mmol), cyclopropylacetylene (0.3 mmol), 9.6 mg (0.015 mmol, 20%) [Cp*RhCl 2 ] 2 , 26.3 mg (0.03 mmol) sodium acetate, 55.2 mg (0.3 mmol) potassium hexafluorophosphate, and then 6.0 mL of a 1:1 mixture of t-BuOH and distilled water;

[0052] 2. Place the reaction tube in a preheated 110°C sand bath, use a carbon rod as the anode and a platinum sheet as the cathode, connect the electrochemical workstation and power on for 2 hours, remove the reaction from the heat source, then add dichloromethane, transfer to a round-bottom flask, use a rotary evaporator to remove the solvent, and pass ethyl acetate / petroleum ether = 1:4 through a silica gel column to obtain 28 mg of the target product with a yield of 43%.

[0053] Example 4

[0054] N-(1-Acetamido-2-methylbenzene)-1H-indole Synthesis method:

[0055] 1. In a pre-dried 25 mL three-necked flask equipped with a magnetic pole, add acetophenylhydrazine (0.6 mmol), 3-ethynyltoluene (0.3 mmol), 9.6 mg (0.015 mmol, 20%) [Cp*RhCl 2 ] 2 , 26.3 mg (0.03 mmol) sodium acetate, 55.2 mg (0.3 mmol) potassium hexafluorophosphate, and then 6.0 mL of a 1:1 mixture of t-BuOH and distilled water;

[0056] 2. Place the reaction tube in a preheated 100°C sand bath, use a carbon rod as the anode and a platinum sheet as the cathode, connect the electrochemical workstation and energize the reaction for 2.5 hours, remove the reaction from the heat source, then add dichloromethane, transfer to a round-bottom flask, use a rotary evaporator to remove the solvent, and pass ethyl acetate / petroleum ether = 1:4 through a silica gel column to obtain 28 mg of the target product with a yield of 26%.

[0057] It should be understood that the application of the present invention is not limited to the above examples. For ordinary technicians in this field, improvements or changes can be made based on the above description. All these improvements and changes should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization, characterized in that: Includes steps: Adding acetylphenylhydrazine derivative, alkyne derivative, [Cp*RhCl2]2, sodium acetate, potassium hexafluorophosphate, t-BuOH and distilled water into a container equipped with a magnetic particle to obtain a mixed reaction solution; The mixed reaction liquid is placed in a sand bath preheated to a predetermined temperature, a carbon rod is used as an anode, a platinum sheet is used as a cathode, one end of the cathode and the anode are inserted into the mixed reaction liquid at intervals, and the other ends of the cathode and the anode are connected to an electrochemical workstation to construct an electro-oxidation cyclization system; The electrochemical workstation is powered on for a predetermined reaction time to obtain a 1-aminoindole derivative.

2. The method for synthesizing 1-aminoindole derivatives by electrooxidative cyclization according to claim 1, characterized in that: The chemical structural formula of the acetophenylhydrazine derivative is: Wherein, R1-R4 are independently selected from one of hydrogen, halogen, alkyl, methoxy and cyano, and R5 is aryl.

3. The method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization according to claim 1, characterized in that: The structural formula of the alkyne derivative is: Wherein, R6-R7 are independently selected from one of an alkyl group and an aromatic group.

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

1.

5. 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, wherein the predetermined temperature is 90-110°C.

6. 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 to react for a predetermined time, the predetermined time is 2-3 hours.

7. The method for synthesizing 1-aminoindole derivatives by electro-oxidative cyclization according to claim 1, characterized in that: After the electrochemical workstation is powered on for a predetermined reaction time, the following steps are further included: The product solution obtained after the reaction was removed from the sand bath, and then dichloromethane was added to the product solution and transferred to a round-bottom flask; The solvent in the round-bottom flask is removed by a rotary evaporator, and the target product is obtained by passing the mixture through a silica gel column, that is, a 1-aminoindole derivative is prepared.

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