Synthesis method of light-promoted 9H-carbazole-9-formaldehyde
The synthesis of 9H-carbazole-9-carbaldehyde using a photocatalyst and oxygen under visible light solves the problems of harsh reaction conditions and pollution in existing technologies, achieving efficient, green, and economical synthesis of N-formylcarbazole, which is suitable for drug synthesis.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-26
- Publication Date
- 2026-04-10
AI Technical Summary
Existing methods for synthesizing 9H-carbazole-9-formaldehyde suffer from problems such as low atom economy, harsh reaction conditions, use of toxic reagents or precious metal catalysts, high energy consumption, and poor selectivity control, making it difficult to achieve green and economical large-scale production.
A photocatalyzed reaction is employed, using non-metallic catalysts such as 4CzIPN to react with oxygen under visible light to generate 9-[(trimethylsilyl)methyl]-9H-carbazole. N-formylcarbazole derivatives are then constructed via a photo-oxidation-reduction desilication mechanism, avoiding high temperature and high pressure and simplifying the operation process.
It achieves green and environmentally friendly high-efficiency synthesis, reduces energy consumption, avoids heavy metal pollution, is suitable for large-scale production, has high yield and high purity, and is applicable to drug synthesis.
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Figure CN121824401A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application relates to the technical field of organic synthesis, in particular to a synthesis method of photo-promoted 9H-carbazole-9-formaldehyde. BACKGROUND
[0002] 9H-carbazole-9-formaldehyde is a key structural unit widely existing in drug molecules and bioactive compounds. At present, there are various methods for synthesizing such compounds, but most of them have problems such as low atom economy, harsh reaction conditions, use of toxic reagents or solvents, dependence on noble metal catalysts, high energy consumption and the like, which are contrary to the principles of green chemistry and sustainable development. The main challenges of the existing synthesis methods are as follows: 1. Low atom economy: many methods rely on stoichiometric oxidants (such as peroxides, high-valence iodine reagents, metal oxygen reagents, etc.), which produce a large amount of by-products, and the atom utilization rate is low. Some reactions use pre-functionalized reagents (such as pre-synthesized formate, Vilsmeier reagent, etc.), which increase the synthesis steps and waste generation; 2. Use of harmful or restricted reagents: common methods use toxic halogenated reagents (such as POCl3, CCl3Br); 3. Some systems rely on noble metal catalysts (such as rhodium, iridium, etc.), which are high in cost and may cause metal residual pollution; 4. Harsh reaction conditions: firstly, most catalytic methods require high temperature (such as 150-190°C), high-pressure hydrogen or long-time reaction (24-48 hours). Secondly, some photocatalytic systems require specific wavelength light sources (such as UV-A), which are complex to operate and high in energy consumption; 5. Poor selectivity control and many side reactions: in the reductive formylation of N-heteroarenes, over-reduction (such as the generation of tetrahydroquinoline) or dehalogenation is easy to occur. When DMF is used as a C1 source, benzene ring formylation rather than N-formylation may occur, especially for substrates with steric hindrance. For multifunctional substrates, chemical selectivity and regioselectivity are still difficult to accurately control; 6. Dependence on catalysts and additives: many methods need to use ligands, additives or bases (such as NaH, t-BuOK), which increase the complexity of the system and the difficulty of purification. The synthesis steps of some catalysts are complicated or the stability is poor, which is difficult to apply on a large scale.
[0003] In summary, how to design a reaction system in which oxygen plays a dual role of terminal oxidant and formyl group source, and realize the maximum utilization of reaction reagents, is an important direction of current related research; and the development of a new method for synthesizing N-formyl carbazole with high atom economy, mild reaction conditions, green and environmentally friendly reagents, inexpensive and recyclable catalysts (the method is referred to as a green method for synthesizing N-formyl carbazole) Figure 1 ) not only is a key challenge to be broken through in the field, but also is the core problem to be solved by the present application. SUMMARY
[0004] To address the aforementioned technical problems, the present invention aims to provide a photocatalyzed synthesis method for 9H-carbazole-9-carbaldehyde. The reaction conditions are mild (room temperature), eliminating the need for high temperatures and reducing energy consumption; a non-metallic catalyst is used, avoiding heavy metal pollution and making the method environmentally friendly.
[0005] To achieve the above objectives, the present invention is implemented through the following technical solution: a photocatalyzed synthesis method of 9H-carbazole-9-formaldehyde, characterized in that: 9-[(trimethylsilyl)methyl]-9H-carbazole, PC catalyst and solvent are added to a reaction flask, and after the addition is complete, air or oxygen is injected into the reaction flask, and the reaction flask is irradiated under visible light to obtain the product.
[0006] In the above scheme: the PC catalyst is 4CzIPN, 3CzCIIPN, fac-Ir(ppy)3, 4CzPN, 4CzTPN, TPT, 4CzTPN, t-Bu-4CzIPN, 3DPAFIPN, Ph-4CzIPN, EoSin Y, Rhodamine B, Fluorescein, [Acr-Mes-Me] + BF4 - One of the types of Riboflavin.
[0007] In the above scheme, the amount of PC catalyst added is 1.5%-6% of the molar amount of 9-[(trimethylsilyl)methyl]-9H-carbazole.
[0008] In the above scheme, the solvent is one of dichloromethane, chloroform, toluene, tetrahydrofuran, xylene, and DMF.
[0009] In the above scheme: the amount of solvent added is 6-20 mL / mol 9-[(trimethylsilyl)methyl]-9H-carbazole
[0010] In the above procedure: after the reaction is complete, the solution is diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate is collected. The solvent is evaporated from the filtrate to obtain the initial product, which is then subjected to rapid column chromatography to obtain the final product. The eluent is ethyl acetate / petroleum ether at a volume ratio of 1:10. The volume ratio of solvent to ethyl acetate dilution is 1:2-1:10.
[0011] In the above scheme: the visible light is blue light or sunlight.
[0012] In the above scheme, the pressure of air or oxygen injected into the reaction flask is 0.8-1 atm.
[0013] like Figure 2 As shown, the reaction mechanism of the present invention is as follows:
[0014] The photocatalyst generates an excited state under light excitation, and then activates compound 1 to generate a free radical intermediate A and a free radical anion photocatalyst through a single electron transfer process. The intermediate A couples with the superoxide anion radical generated by the reduction of oxygen to form intermediate B. The intermediate B undergoes beta cleavage to form the target product 2. At the same time, the free radical anion photocatalyst is reduced to the ground state photocatalyst. The whole process does not need metal participation, the conditions are mild, and it is environmentally friendly.
[0015] Compared with the prior art, the present application has the following beneficial effects:
[0016] 1. Green and environmentally friendly: driven by visible light, mild reaction conditions (room temperature), no need for high temperature, reduced energy consumption; using a non-metal catalyst, avoiding heavy metal pollution, in line with the principles of green chemistry; using oxygen as the only oxidizing agent, without the need to use stoichiometric inorganic oxidizing agents; the reaction is carried out under visible light irradiation, with lower energy consumption and lower radiation damage.
[0017] 2. High efficiency and high selectivity: through the photooxidation-reduction desiliconization mechanism, the nitrogen-containing ortho-methylene is effectively activated, high chemical selectivity is achieved, and N-formylcarbazole derivatives can be efficiently constructed.
[0018] 3. Simple operation: the reaction system is simple, no special equipment is needed, the post-reaction treatment is convenient, and it is suitable for large-scale production.
[0019] 4. Wide application prospect: the obtained 9-[(trimethylsilyl)methyl]-9H-carbazole can be used as a key building block for drug synthesis (such as anticancer drugs), and has important medical research and industrialization value. BRIEF DESCRIPTION OF DRAWINGS
[0020] Figure 1 It is a schematic diagram for realizing the construction of N-formylcarbazole skeleton fragments by a light-promoted oxidation strategy.
[0021] Figure 2 It is a schematic diagram of the reaction mechanism.
[0022] Figure 3 It is 1 H NMR spectrum
[0023] Figure 4 It is 13 C NMR spectrum.
[0024] Figure 5 It is the structural formula of each catalyst. DETAILED DESCRIPTION
[0025] The present application will be further described below in conjunction with examples.
[0026] The eluent used in the present application is ethyl acetate / petroleum ether with a volume ratio of 1:10.
[0027] Example 1
[0028]
[0029] Compound 1 (9-[(trimethylsilyl)methyl]-9H-carbazole) (0.30 mmol, 76.0 mg) and PC catalyst 4CzIPN (1.5% of the substrate molar amount, 1.2 mg) were placed in solvent DCE (5 mL), after the addition of the reaction tank was injected 1 atm of O2 and 0.8 atm of O2, then the reaction mixture was placed under blue light irradiation stirring. After 24 hours, it was diluted with 10 mL of ethyl acetate and filtered through celite, collecting the filtrate. The filtrate was removed by solvent through a rotary evaporator, obtaining the initial product, then by flash column chromatography (eluent ethyl acetate / petroleum ether), obtaining the N-formyl carbazole product 2. The yield was 93%, 91.8% respectively, with a purity greater than 95%.
[0030] NMR characterization data:
[0031] 1 H NMR (500 MHz, Chloroform-d): δ 9.68 (s, 1H), 8.58 (s, 1H), 7.97(d, J = 7.6 Hz, 2H), 7.71 (s, 1H), 7.40-7.71 (m, 4H).
[0032] 13 C NMR (126 MHz, Chloroform-d): δ 157.46, 127.83, 127.10, 126.20,124.72, 124.35, 120.81, 119.86, 116.84, 109.96.
[0033] Example 2
[0034] Compound 1 (9-[(trimethylsilyl)methyl]-9H-carbazole) (0.30 mmol, 76.0 mg) and PC catalyst 4CzIPN (1.5% of the substrate molar amount, 1.2 mg) were placed in solvent DCE (5 mL), after the addition of the reaction tank was injected 1 atm of air, then the reaction mixture was placed under blue light irradiation stirring. After 24 hours, it was diluted with 10 mL of ethyl acetate and filtered through celite, collecting the filtrate. The filtrate was removed by solvent through a rotary evaporator, obtaining the initial product, then by flash column chromatography (eluent ethyl acetate / petroleum ether), obtaining the N-formyl carbazole product 2 (50.1% yield). The purity was greater than 94%.
[0035] Example 3
[0036] Compound 1 (0.30 mmol, 76.0 mg) and PC catalyst 4CzIPN (3.0% of the substrate molar quantity, 2.4 mg) were placed in solvent DCE (5 mL), after the addition was completed, the reaction tank was injected with 1 atm of O2, and then the reaction mixture was placed under blue light for irradiation and stirring. After 24 hours, it was diluted with 10 mL of ethyl acetate and filtered through diatomite, and the filtrate was collected. The filtrate was removed by a rotary evaporator to obtain the initial product, and then fast column chromatography (eluent ethyl acetate / petroleum ether, volume ratio 1:1) was used to obtain the N-formyl carbazole product 2 (90% yield). The purity was greater than 95%.
[0037] Example 4
[0038] Compound 1 (0.30 mmol, 76.0 mg) and PC catalyst 4CzIPN (6.0% of the substrate molar quantity, 4.1 mg) were placed in solvent DCE (3 mL), after the addition was completed, the reaction tank was injected with 1 atm of O2, and then the reaction mixture was placed under blue light for irradiation and stirring. After 24 hours, it was diluted with 20 mL of ethyl acetate and filtered through diatomite, and the filtrate was collected. The filtrate was removed by a rotary evaporator to obtain the initial product, and then fast column chromatography (eluent ethyl acetate / petroleum ether) was used to obtain the N-formyl carbazole product 2 (80% yield). The purity was greater than 95%.
[0039] Example 5
[0040] Compound 1 (0.30 mmol, 76.0 mg) and PC catalyst 3DPAFIPN (6.0% of the substrate molar quantity, 3.9 mg) were placed in solvent DCE (2 mL), after the addition was completed, the reaction tank was injected with 1 atm of O2, and then the reaction mixture was placed under blue light for irradiation and stirring. After 24 hours, it was diluted with 10 mL of ethyl acetate and filtered through diatomite, and the filtrate was collected. The filtrate was removed by a rotary evaporator to obtain the initial product, and then fast column chromatography (eluent ethyl acetate / petroleum ether) was used to obtain the N-formyl carbazole product 2 (40% yield), with a purity greater than 95%
[0041] Example 6
[0042] Compound 1 (0.30 mmol, 76.0 mg) and PC catalyst 4CzTPN (6.0% of the substrate molar quantity, 3.9 mg) were placed in solvent chloroform (2 mL), after the addition was completed, the reaction tank was injected with 1 atm of O2, and then the reaction mixture was placed under blue light for irradiation and stirring. After 24 hours, it was diluted with 20 mL of ethyl acetate and filtered through diatomite, and the filtrate was collected. The filtrate was removed by a rotary evaporator to obtain the initial product, and then fast column chromatography (eluent ethyl acetate / petroleum ether) was used to obtain the N-formyl carbazole product 2 (89% yield). The purity was greater than 95%.
[0043] Example 7
[0044] Compound 1 (0.30 mmol, 76.0 mg) and PC catalyst Rhodamine B (6.0% of the substrate molar quantity, 2.9 mg) were placed in solvent DCE (2 mL), after the addition, the reaction tank was injected with 1 atm O2, and then the reaction mixture was placed under blue light for irradiation and stirring. After 24 hours, it was diluted with 20 mL of ethyl acetate and filtered through diatomite, and the filtrate was collected. The filtrate was removed by a rotary evaporator to obtain the primary product, and then fast column chromatography (eluent: ethyl acetate / petroleum ether) was performed to obtain the N-formyl carbazole product 2 (78% yield). The purity was greater than 95%.
[0045] Example 8
[0046] Compound 1 (0.30 mmol, 76.0 mg) and PC catalyst 4CzIPN (6.0% of the substrate molar quantity, 4.1 mg) were placed in solvent DMF (2 mL), after the addition, the reaction tank was injected with 1 atm O2, and then the reaction mixture was placed under blue light for irradiation and stirring. After 24 hours, it was diluted with 20 mL of ethyl acetate and filtered through diatomite, and the filtrate was collected. The filtrate was removed by a rotary evaporator to obtain the primary product, and then fast column chromatography (eluent: ethyl acetate / petroleum ether) was performed to obtain the N-formyl carbazole product 2 (40% yield). The purity was greater than 95%.
[0047] Example 9
[0048] Compound 1 (0.30 mmol, 76.0 mg) and PC catalyst 4CzIPN (6.0% of the substrate molar quantity, 4.1 mg) were placed in solvent toluene (2 mL), after the addition, the reaction tank was injected with 1 atm O2, and then the reaction mixture was placed under blue light for irradiation and stirring. After 24 hours, it was diluted with 20 mL of ethyl acetate and filtered through diatomite, and the filtrate was collected. The filtrate was removed by a rotary evaporator to obtain the primary product, and then fast column chromatography (eluent: ethyl acetate / petroleum ether) was performed to obtain the N-formyl carbazole product 2 (53% yield). The purity was greater than 95%.
[0049] Example 10
[0050] Compound 1 (0.30 mmol, 76.0 mg) and PC catalyst 4CzIPN (1.5% of the substrate molar quantity, 1.2 mg) were placed in solvent DCE (5 mL), after the addition was completed, the reaction tank was injected with 1 atm O2, then the reaction mixture was placed under solar light irradiation and stirring. After 24 hours, it was diluted with 10 mL of ethyl acetate and filtered through diatomite, the filtrate was collected. The solvent was removed by a rotary evaporator to obtain the initial product, then it was subjected to flash column chromatography (eluent: ethyl acetate / petroleum ether) to obtain the N-formylcarbazole product 2 (60% yield). The purity was greater than 90%.
[0051] Example 11
[0052] The rest was the same as Example 1, except that the catalysts used were: 3CzCIIPN, 4CzPN, 4CzTPN, TPT, t-Bu-4CzIPN, Ph-4CzIPN, EoSin Y, Fluorescein, [Acr-Mes-Me] + BF4 - , Riboflavin. The yields were: 90%, 93%, 89%, 20%, 85%, 87%, 30%, 43%, 15%, 65%, respectively.
[0053] Although embodiments of the present application have been shown and described, it is to be understood that various modifications, substitutions, replacements and variations can be made to these embodiments without departing from the principles and spirit of the present application, the scope of which is defined by the appended claims and their equivalents.
Claims
1. A method for the synthesis of photoinduced 9H-carbazole-9-carbaldehyde, characterized by: 9-[(trimethylsilyl)methyl]-9H-carbazole, PC catalyst and solvent are added into a reaction bottle, after the addition, air or oxygen is injected into the reaction bottle, and the reaction bottle is subjected to reaction under visible light irradiation to obtain a product.
2. The method of claim 1, wherein the photoinduced synthesis of 9H-carbazole-9- carbaldehyde is characterized by: The PC catalyst is one of 4CzIPN, 3CzCIIPN, fac-Ir(ppy)3, 4CzPN, 4CzTPN, TPT, 4CzTPN, t-Bu-4CzIPN, 3DPAFIPN, Ph-4CzIPN, EoSin Y, Rhodamine B, Fluorescein, [Acr-Mes-Me] + BF4 - one of Riboflavin.
3. The method of claim 1 or 2, wherein the method is characterized by: The PC catalyst is added in an amount of 1.5%-6% of the molar amount of 9-[(trimethylsilyl)methyl]-9H-carbazole.
4. The method of claim 3, wherein the photoinduced synthesis of 9H-carbazole-9- carbaldehyde is characterized by: The solvent is one of dichloromethane, chloroform, toluene, tetrahydrofuran, dimethylbenzene and DMF.
5. The method of claim 4, wherein the method is characterized in that: The solvent is added in an amount of 6-20 mL / 1 mol of 9-[(trimethylsilyl)methyl]-9H-carbazole.
6. The method of claim 5, wherein the method is characterized in that: After the reaction, the product is diluted with ethyl acetate, filtered through diatomite, the filtrate is collected, and the solvent is evaporated from the filtrate to obtain a primary product, and then the product is obtained through flash column chromatography, and the eluent is ethyl acetate / petroleum ether with a volume ratio of 1:
10.
7. The method of claim 1, wherein the photoinduced synthesis of 9H-carbazole-9- carbaldehyde is represented by the following scheme: ###0001### Scheme 1 The visible light is blue light or sunlight.
8. The method of claim 1, wherein the photoinduced synthesis of 9H-carbazole-9- carbaldehyde is characterized by: The pressure of air or oxygen injected into the reaction bottle is 0.8-1 atm.