A method for photocatalytic synthesis of aromatic secondary amine compounds
Through photocatalytic method, photoreaction of p-toluenesulfonylhydrazone derivatives and amines was carried out in the presence of alkali, and N-H insertion was achieved to synthesize aryl secondary amine compounds, solving the limited range of metal catalysts and substrates in the prior art. Problem, efficient and green amine compounds synthesis has been achieved.
Patent Information
- Application Number
- CN202310364042.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-04-07
- Publication Date
- 2025-02-11
- Estimated Expiration
- 2043-04-07
AI Technical Summary
The prior art When introducing C-N bonding to synthesize amine compounds, metal catalysts are required, and the substrate range is limited, resulting in poor structural diversity and instability and unavailability problems.
Using photocatalytic method, p-toluenesulfonylhydrazone derivatives and amines are used as raw materials. In the presence of alkali, light reaction in the organic solvent is achieved by slowly releasing the donor/donor diazonium substances and reacting with the multifunctional amine to achieve N-H insertion and synthesis of aromatic aromatics. Secondary amine compounds.
It realizes a safe, green and efficient N-H insertion synthetic amine compounds, avoids the use of metal catalysts, expands the substrate range, improves yield, and is environmentally friendly, suitable for the construction of β-amino acids.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for photocatalytically synthesizing aromatic secondary amine compounds. Background Art
[0002] It is well known that nitrogen-containing molecules (such as amino acids, alkaloids, and N-heterocyclic compounds) have a wide range of biological and pharmacological activities. It is reported that more than 85% of FDA-approved drugs contain nitrogen atoms, and the percentage and frequency of nitrogen heterocycles continue to increase. Multifunctional amine products are ubiquitous skeletons in natural products. Therefore, the development of simple and sustainable strategies to introduce CN bonds to synthesize amine compounds has become a high demand.
[0003] In recent years, chemists have worked hard to develop simple and diverse strategies to introduce C-N bonds, such as eTM-catalyzed C-N cross-coupling reactions, reductive amination and electrophilic amination, and the palladium-catalyzed Csp- 2 -N coupling is the most commonly used method to introduce CN bonds.
[0004] In addition, based on the carbene NH insertion to form C(sp 3 )-N bonds develop rapidly. Usually, metal carbenes are first formed from diazo or diazo precursors, and then react with molecules with NH bonds to generate NH insertion products. However, metal catalysts such as rhodium, copper, ruthenium, silver and iron catalysts are indispensable for the generation of metal carbenes and promoting the reaction, and the substrate range is relatively limited to alkyl diazo esters. At the same time, donors without electron-withdrawing groups and donor / donor-type diazo compounds are rarely used in carbene-based NH insertion due to the instability and unavailability of these molecules, resulting in poor structural diversity of nitrogen-containing molecules.
[0005] Therefore, it is highly desirable to develop more sustainable and benign methods to achieve C-N bond formation without the need for metal catalysts and with a broad substrate scope including donor-type diazo compounds or precursors. Summary of the invention
[0006] The present invention is based on the above research, and aims to provide a safe, green and efficient method for synthesizing aromatic secondary amine compounds by photocatalytic NH insertion. Under the protection of inert gas, p-toluenesulfonylhydrazone derivatives and amines are used as raw materials, and in the presence of a base, they are irradiated and reacted under a light source in an organic solvent, and aromatic secondary amine compounds are obtained after separation and purification; the present invention can slowly release donors / donor heavy nitrogen substances, and then react with multifunctional amines to achieve NH insertion; the raw materials are cheap and easy to obtain, the operation is simple, and it is green and environmentally friendly, providing a new way for NH insertion to synthesize amine compounds, and this strategy can also be applied to the construction of β-amino acids.
[0007] In order to achieve the above object, the technical solution adopted by the present invention is as follows:
[0008] The present invention uses ketone, p-toluenesulfonyl hydrazine, amine and base as raw materials, or directly uses p-toluenesulfonyl hydrazone derivatives, amine and base as raw materials to obtain products through photocatalysis to achieve NH insertion into amine compounds. The methods of synthesizing the NH insertion products using the two raw materials are basically the same. When only the first raw material is used, the ketone and p-toluenesulfonyl hydrazine are sealed and stirred first, and then the synthesis process is carried out.
[0009] The method for photocatalytically synthesizing aromatic secondary amine compounds of the present invention comprises the following steps: using a p-toluenesulfonylhydrazone derivative 1 and an amine 2 as raw materials, and subjecting them to light irradiation reaction in an organic solvent in the presence of a base to obtain an aromatic secondary amine compound 3.
[0010] The reaction equation is as follows:
[0011]
[0012] in:
[0013] In the p-toluenesulfonylhydrazone derivative 1, R 1 and R 2 Each is independently selected from H, C1-C4 alkyl, benzyl and its substituents, phenylfuran and its substituents, benzothiophene and its substituents, indole and its substituents, phenyl and its substituents, naphthyl and its substituents; the substituent is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonylalkoxy, methylenedioxy, Boc, halogen, phenoxy; or R 1 -R 2 Together they form a ring structure through carbon, oxygen, sulfur or nitrogen atoms;
[0014] In the amine 2, R 3 and R 4 Each is independently selected from H, C1-C6 alkyl, allyl, benzyl, phenyl / biphenyl and its substituents, pyridine and its substituents, quinoline / quinoxaline and its substituents, pyrimidine and its substituents; the substituent is C1-C4 alkyl, C1-C4 alkoxy, N-Boc piperazine, halogen; or R 1 -R 2 Together they form a ring structure through carbon, oxygen, sulfur or nitrogen atoms.
[0015] Furthermore, in the above technical solution, the typical structure of the p-toluenesulfonylhydrazone derivative 1 is:
[0016]
[0017] Furthermore, in the above technical solution, the typical structure of the amine 21 is:
[0018]
[0019] Furthermore, in the above technical solution, the base is selected from one or more of DBU, DBN, DABCO, DTHP, Cs2CO3, K2CO3, K2PO4, Na2CO3 or NaHCO3. The key to the reaction is the process of passing through the electron donor-acceptor (EDA) complex; using UV / Vis absorption spectrum detection, it is found that the most suitable base is DBN, TBD, DBU or Cs2CO3.
[0020] Furthermore, in the above technical solution, the organic solvent is selected from any one or more combinations of γ-valerolactone, dichloromethane, acetonitrile, tetrahydrofuran and ethyl acetate. Preferably, the organic solvent is dichloromethane.
[0021] Furthermore, in the above technical solution, the molar ratio of the p-toluenesulfonylhydrazone derivative 1, the amine 2 and the base is 1:1-10:1-3.
[0022] Furthermore, in the above technical solution, the reaction temperature is 20-35°C; and the reaction time is 4-20 hours.
[0023] Furthermore, in the above technical solution, the wavelength of the light source is 400-460nm; the distance between the light source and the reaction tube is 2-6 cm.
[0024] Furthermore, in the above technical solution, the reaction is carried out under an inert atmosphere.
[0025] Furthermore, in the above technical solution, the p-toluenesulfonylhydrazone derivative 1 is obtained by reacting a carbonyl compound (aldehyde or ketone) with p-toluenesulfonylhydrazone in an alcohol solvent. Among them, the typical aldehyde or ketone structure is as follows:
[0026]
[0027] Furthermore, in the above technical scheme, the post-treatment operation is: after the reaction is completed, the reaction product is extracted with ethyl acetate and water, dried with anhydrous sodium sulfate, and then the solvent is removed, and separated and purified by column chromatography to obtain an aromatic secondary amine compound.
[0028] Beneficial effects of the present invention
[0029] The present invention uses ketone, p-toluenesulfonyl hydrazine and amine or p-toluenesulfonyl hydrazone derivative and amine as main raw materials, and has the characteristics of low irritation and easy acquisition of raw materials. The key to the reaction is to slowly release the donor / donor heavy nitrogen substance, and then react with the multifunctional amine to achieve NH insertion. The reaction process is at room temperature and pressure, and the NH insertion amine compound is synthesized by photocatalytic reaction. Not only is the synthesis process simple, the synthesis yield is significantly improved, and the environmental pollution after the reaction is small, which is green and environmentally friendly. The raw materials are cheap and easy to obtain, the operation is simple, and it is green and environmentally friendly, which provides a new way for the synthesis of NH insertion amine compounds. At the same time, this strategy can also be applied to the construction of β-amino acids. DETAILED DESCRIPTION
[0030] The implementation of the present invention is described in detail below in conjunction with the embodiments of the present invention. The following embodiments are implemented on the premise of the technical solution of the present invention, and provide detailed implementation methods and specific operating processes, but the protection scope of the present invention is not limited to the following embodiments.
[0031] Example 1 Condition Optimization Experiment:
[0032] In a dry reaction tube, add a magnet and p-toluenesulfonylhydrazone derivative 1a (0.2mmol), replace argon three times with a double-row tube, then add 4-amino-2-chloropyridine 2a (1.0mmol, 5.0eq), DBN (0.3mmol, 1.5eq) and 2.0mL dichloromethane. After sealing, illuminate under a 427nm Kessil light source (40W), the light source is about 4cm away from the reaction tube, and the fan or low-temperature reactor is used to cool down, and the temperature is controlled at 25-35℃. Stop the reaction after 6 hours, and use 1,3,5-trimethoxybenzene as an internal standard to calculate the yield of product 3a (non-isolated yield).
[0033]
[0034]
[0035]
[0036] Example 2
[0037] In a dry reaction tube, add a magnet and p-toluenesulfonylhydrazone derivative 1 (0.2 mmol), replace argon three times with a double-row tube, then add 4-amino-2-chloropyridine 2a (1.0 mmol, 5.0 eq), DBN (0.3 mmol, 1.5 eq) and 2.0 mL of dichloromethane. After sealing, illuminate under a 427 nm Kessil light source (40 W), the light source is about 4 cm away from the reaction tube, and the fan or low-temperature reactor is used to cool down, and the temperature is controlled to be 25-35 ° C. After 6 hours, the reaction is stopped, extracted with ethyl acetate and water, dried with anhydrous sodium sulfate, and the solvent is removed by spin, and separated and purified by column chromatography to obtain NH-inserted aromatic secondary amine compound 3. The results of different reaction substrates are shown below:
[0038]
[0039]
[0040] Example 3
[0041] Changing different reaction materials 1 and 2 to conduct substrate experiments:
[0042] In a dry reaction tube, add a magnet and p-toluenesulfonylhydrazone derivative 1 (0.2 mmol), replace argon three times with a double-row tube, then add amine 2 (1.0 mmol, 5.0 eq), DBN (0.3 mmol, 1.5 eq) and 2.0 mL of dichloromethane. After sealing, illuminate under a 427 nm Kessil light source (40 W), the light source is about 4 cm away from the reaction tube, and the fan or low-temperature reactor is used to cool down, and the temperature is controlled to be 25-35 ° C. After 6 hours, stop the reaction, extract with ethyl acetate and water, dry with anhydrous sodium sulfate, and then spin-dry the solvent, separate and purify by column chromatography to obtain NH-inserted aromatic secondary amine compound 3. The reaction results are as follows:
[0043]
[0044] The preferred embodiments of the present invention have been specifically described above, but the present invention is not limited to the embodiments. Those skilled in the art may make various equivalent modifications or substitutions without violating the spirit of the present invention. These equivalent modifications or substitutions are all included in the scope defined by the claims of this application.
Claims
1. A method for photocatalytic synthesis of aromatic secondary amine compounds, characterized in that: The method comprises the following steps: using a p-toluenesulfonylhydrazone derivative 1 and an amine 2 as raw materials, and subjecting them to light-induced reaction in an organic solvent in the presence of a base to obtain an aromatic secondary amine compound 3; the reaction equation is as follows: The p-toluenesulfonylhydrazone derivative 1 is selected from the following structures: The amine 2 is selected from the following structures: The base is selected from DBU or DBN, and the wavelength of light is 427 nm.
2. The method for photocatalytic synthesis of aromatic secondary amine compounds according to claim 1, characterized in that: The organic solvent is selected from any one or more combinations of γ-valerolactone, dichloromethane, acetonitrile, tetrahydrofuran and ethyl acetate.
3. The method for photocatalytic synthesis of aromatic secondary amine compounds according to claim 1, characterized in that: The molar ratio of the p-toluenesulfonylhydrazone derivative 1, the amine 2 and the base is 1:1-10:1-3.
4. The method for photocatalytic synthesis of aromatic secondary amine compounds according to claim 1, characterized in that: The reaction temperature is 20-35°C; the reaction time is 4-20 hours.
5. The method for photocatalytic synthesis of aromatic secondary amine compounds according to claim 1, characterized in that: The light source is 2-6 cm away from the reaction tube.
6. The method for photocatalytic synthesis of aromatic secondary amine compounds according to any one of claims 1 to 5, characterized in that: The reaction was carried out under an inert atmosphere.
7. The method for photocatalytic synthesis of aromatic secondary amine compounds according to claim 1, characterized in that: The p-toluenesulfonylhydrazone derivative 1 is obtained by reacting a carbonyl compound with p-toluenesulfonylhydrazone in an alcohol solvent.
8. The method for photocatalytic synthesis of aromatic secondary amine compounds according to claim 1, characterized in that: After the reaction is completed, the reaction product is extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, and then the solvent is removed by spin, and the product is separated and purified by column chromatography to obtain an aromatic secondary amine compound.