Method for efficiently synthesizing 10H-indolo [1, 2-a] indole compound

Abstract

The invention provides a method for efficiently synthesizing a 10H-indolo [1, 2-a] indole compound, and belongs to the field of organic synthesis. According to the method, starting raw materials containing carbonyl and indole structures are utilized, under catalytic mediation of metal molybdenum, triphenylphosphine serves as an oxygen acceptor, deoxidation cyclization and isomerization reaction in molecules are successfully achieved, and therefore the 10H-indolo [1, 2-a] indole compounds are smoothly converted. According to the preparation method, the reaction rate is high, the operation steps are simple and clear, the synthesis efficiency is remarkably improved, more importantly, used reaction reagents are wide, easy to obtain and economical in cost, great convenience is provided for industrial large-scale production, the cost is reduced, and the remarkable cost advantage is achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a method for efficiently synthesizing a 10H-indolo[1,2-a]indole compound. Background Art

[0002] As a class of fused-ring aromatic hydrocarbons with unique electronic structures and molecular symmetries, 10H-indolo[1,2-a]indole and its derivatives have demonstrated remarkable application potential in numerous fields. In drug development, they serve as key components of pharmacophores or structural units, providing broad opportunities for the design and synthesis of new drugs. In organic synthesis, these compounds serve as important intermediates, widely used in the construction and modification of complex organic molecules. There are some reports on the synthesis of 10H-indolo[1,2-a]indole compounds. The research team successfully synthesized 10H-indolo[1,2-a]indole by using copper-mediated intramolecular CH functionalization cyclization reaction of indole. The reaction equation is as follows. Another example is that Wang's group proposed another method for synthesizing 10H-indolo[1,2-a]indole compounds. This method uses trimethylsilyldiazomethane as a carbene source and, under palladium catalysis, metal carbene migration insertion and C(sp 2 )-H bond activation to produce a [4+1] cyclization reaction, which is characterized by the simultaneous formation of two different CC bonds on a carbene center. The reaction equation is as follows. For example, Sun's research project achieved the formation of 10H-indolo[1,2-a]indole compounds through intramolecular nucleophilic addition, hydrogen migration, and rearrangement catalyzed by iodine (I2) / zinc iodide (ZnI2). The reaction equation is as follows. Patent CN115043847B discloses a method for preparing 10H-indolo[1,2-a]indole-10-one compounds. This method utilizes a difluorocarbene precursor, a catalyst, a ligand, an additive, and a base. Under an argon atmosphere, the solvent is mixed with an N-aryl indole compound and the mixture is reacted to produce the 10H-indolo[1,2-a]indole-10-one compound. The reported methods have encountered severe challenges when attempting to carry out large-scale industrial production, mainly due to high costs or harsh reaction conditions. The method proposed by the research group not only requires a large excess of K₃PO₄ (up to 2 equivalents) during the reaction, but also requires the use of expensive chiral cyclohexanediamine as a ligand, resulting in significant waste of raw materials and a significant increase in production costs. Similarly, the method proposed by the Wang group uses trimethylsilyldiazomethane as a carbene source and requires the use of expensive tetrakistriphenylphosphine palladium as a catalyst, leading to waste of raw materials and further increasing production costs. More seriously, the diazonium compound produced in this process is potentially explosive, posing a significant safety hazard for industrial production. The method reported by the Sun group using 10H-indolo[1,2-a]indole derivatives requires the substrate olefin to contain two strong electron-withdrawing groups to ensure the reaction proceeds smoothly. More importantly, the reaction uses iodine as a catalyst, which is highly toxic and can cause poisoning by inhalation, ingestion, or skin contact. It is also prone to corroding metals and sealing materials, accelerating equipment aging, and increasing the risk of leakage, making this method unsuitable for industrial production. Patent CN 115043847B reports a method for preparing 10H-indolo[1,2-a]indole-10-one compounds. The method requires the use of expensive palladium ligands (such as tetrakistriphenylphosphine palladium) and excess inorganic base during the reaction, significantly increasing production costs. Furthermore, the patent does not provide specific chromatographic analysis data for the target compound, hindering subsequent research and application. In summary, these methods all exhibit significant limitations and challenges when applied to large-scale production. Therefore, it is necessary to explore more efficient, mild, low-cost, and simple-to-operate methods to synthesize 10H-indolo[1,2-a]indole compounds. Summary of the Invention

[0003] Technical problems to be solved: In response to the above-mentioned technical problems, the purpose of the present invention is to provide a method for efficiently synthesizing 10H-indolo[1,2-a]indole compounds, which belongs to the field of organic synthesis. This method utilizes starting materials containing carbonyl and indole structures, and under the catalytic mediation of metal molybdenum, triphenylphosphine is used as an oxygen acceptor to successfully achieve deoxygenation cyclization and isomerization reactions within the molecule, thereby smoothly converting it into a 10H-indolo[1,2-a]indole compound. The preparation method of the present invention not only has a fast reaction rate, but also has simple and clear operating steps, which significantly improves the synthesis efficiency. More importantly, the reaction reagents used are widely available and cost-effective, which provides great convenience for industrial large-scale production and reduces costs, and has significant cost advantages.

[0004] Technical solution: A method for efficiently synthesizing 10H-indolo[1,2-a]indole compounds, comprising the following steps: Step 1. Molybdenum hexacarbonyl is dissolved in mesitylene, and 3,5-di-tert-butyl-o-benzoquinone is added thereto and reacted at 150-160° C. for 15-20 minutes to prepare a mixed system; Step 2. Add the starting material S1 and PPh3 to the mixed system, react at 150-160°C for 48-60 hours, cool and remove the solvent, and purify to obtain a 10H-indolo[1,2-a]indole compound; The reaction formula for its synthesis is as follows: Reaction mechanism: ① Under heating conditions, hexacarbonylmolybdenum reacts with Kun to generate catalyst intermediate M-1; ② M-1 reacts with the carbonyl oxygen atom in the starting substrate S1 molecule to form a carbene intermediate Int-1. At this time, the indole ring undergoes a carbon-hydrogen insertion reaction to obtain the intermediate Int-2 and the molybdenum catalyst intermediate M-2; ③ Int-2 undergoes an olefin isomerization reaction to generate a 10H-indolo[1,2-a]indole compound P1. At the same time, the molybdenum catalyst intermediate M-2 undergoes a deoxygenation reaction under the action of triphenylphosphine (PPh3) to regenerate the catalyst intermediate M-1. Furthermore, the molecular structure of the starting material S1 in step 1 is as follows: Wherein R is C6H5 or 4-BrC6H4. Furthermore, the molar ratio of the molybdenum hexacarbonyl, 3,5-di-tert-butyl-o-benzoquinone and the starting material S1 is (0.15-0.2):(0.15-0.2):1.0. Furthermore, the molecular structural formula of the 10H-indolo[1,2-a]indole compound in step 2 is any one of the following: A 10H-indolo[1,2-a]indole compound synthesized by the method described in any one of the above. Application of the above-mentioned 10H-indolo[1,2-a]indole compound in drug synthesis. Beneficial effects: 1. The present invention uses a compound containing a carbonyl group and an indole ring as a reaction substrate, utilizes a high-valent molybdenum catalyst as a catalyst, forms a carbene intermediate with the reaction substrate, and synthesizes a 10H-indolo[1,2-a]indole compound through the steps of carbon-hydrogen insertion, internal cyclization-deoxygenation-olefin isomerization. At the same time, the use of hexacarbonyl molybdenum as a catalyst not only significantly reduces the reaction production cost, but also effectively avoids the use of potentially highly hazardous diazo compounds, thereby ensuring the safety of industrial production and providing a more reliable and robust guarantee for large-scale production. 2. The synthesis of 10H-indolo[1,2-a]indole compounds prepared by the present invention can achieve 11-position ketocarbonyl substitution, expand the types of 10H-indolo[1,2-a]indole compounds, and provide a solid data foundation for in-depth research on 10H-indolo[1,2-a]indole compounds. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is the H NMR spectrum of 10H-indolo[1,2-a]indole compound 1 in Example 1; Figure 2 is the C NMR spectrum of 10H-indolo[1,2-a]indole compound 1 in Example 1; Figure 3 is the H NMR spectrum of 10H-indolo[1,2-a]indole compound 2 in Example 2; Figure 4 This is the NMR carbon spectrum of 10H-indolo[1,2-a]indole compound 2 in Example 2. DETAILED DESCRIPTION The present invention will be further described below in conjunction with examples, which are provided to explain the present invention and are not limited to the following examples: Example 1 A method for efficiently synthesizing a 10H-indolo[1,2-a]indole compound comprises the following steps: Step 1. Under nitrogen, add 0.04 mmol Mo(CO)6 (10.6 mg), 0.04 mmol 3,5-di-tert-butyl-o-benzoquinone (8.8 mg), and 2 mL mesitylene to a 10 mL Schlenk reaction tube. Seal the reaction tube and place it at 160°C for 15 min, then cool to room temperature. Step 2. Under nitrogen, 0.2 mmol of substrate S1-1 (65.0 mg) and 0.24 mmol of PPh3 (63.0 mg) were added. The reaction tube was sealed and placed at 160°C for 48 h. After cooling to room temperature, the solvent was removed under vacuum. The molecular structure of the substrate S1-1 is as follows: Step 3. The product was purified by column chromatography (eluent: 5% ethyl acetate / petroleum ether) to obtain 10H-indolo[1,2-a]indole compound 1 (48.5 mg) with a product yield of 80%; The molecular structural formula of the 10H-indolo[1,2-a]indole compound 1 is as follows. Depend on Figure 1 and Figure 2 It can be seen that the NMR data of 10H-indolo[1,2-a]indole compound 1 is: 1 H NMR (400MHz, CDCl3) δ = 8.11 (d, J = 7.8Hz, 1H), 7.88-7.81 (m, 1H), 7.80-7.74 (m, 2H), 7.70 (d, J = 7.9 Hz,1H),7.64-7.56(m,1H),7.56-7.50(m,2H),7.48-7.29(m,4H),7.23-7.16(m,1H),3.91(s,2H); 13 C NMR (100MHz, CDCl3)δ=191.8,150.5,141.2,140.5,133.4,131.4,131.2,131.1,12 8.5,128.1,128.0,125.8,124.0,123.3,122.9,122.6,111.5,111.3,110.9,31.8. Example 2 A method for efficiently synthesizing a 10H-indolo[1,2-a]indole compound comprises the following steps: Step 1. Under nitrogen, add 0.04 mmol Mo(CO)6 (10.6 mg), 0.04 mmol 3,5-di-tert-butyl-o-benzoquinone (8.8 mg), and 2 mL mesitylene to a 10 mL Schlenk reaction tube. Seal the reaction tube and place it at 160°C for 15 min, then cool to room temperature. Step 2. Under nitrogen, 0.2 mmol of substrate S1-2 (80.8 mg) and 0.24 mmol of PPh3 (63.0 mg) were added. The reaction tube was sealed and placed at 160°C for 48 h. After cooling to room temperature, the solvent was removed under vacuum. The molecular structure of the substrate S1-2 is as follows: Step 3. The product was purified by column chromatography (eluent: 5% ethyl acetate / petroleum ether) to obtain 10H-indolo[1,2-a]indole compound 2 (60.6 mg) with a product yield of 78%; The molecular structural formula of the 10H-indolo[1,2-a]indole compound 2 is as follows. Depend on Figure 3 and Figure 4 It can be seen that the NMR data of 10H-indolo[1,2-a]indole compound 2 is: 1 H NMR (400MHz, CDCl3) δ = 7.89 (dd, J = 7.9, 1.5Hz, 1H), 7.66 (dd, J = 8.0, 1.5Hz, 1H), 7.45–7.34 (m, 5H),7.32–7.29(m,1H),7.26–7.21(m,1H),7.05–6.99(m,1H),6.90–6.77(m,1H),4.53(s,2H); 13 C NMR(100MHz, CDCl3)δ=197.4,140.2,137.8,136.2,136.0,132.7,129.6,12 9.4,128.6,128.3,124.7,122.8,122.6,114.6,110.2,102.9,101.1,26.4. Comparative Example 1 The difference between this comparative example and Example 1 is that Mo(CO)6 and 3,5-di-tert-butyl-o-benzoquinone are replaced by Sc(OTf)3. A method for efficiently synthesizing a 10H-indolo[1,2-a]indole compound comprises the following steps: Step 1. Under nitrogen, add 0.04 mmol of Sc(OTf)3 (19.7 mg) and 2 mL of mesitylene to a 10 mL Schlenk reaction tube. Seal the reaction tube and place it at 160°C for 15 min, then cool to room temperature. Step 2. Under nitrogen, 0.2 mmol of substrate S1-1 (65.0 mg) was added, the reaction tube was sealed and placed at 160°C for further reaction for 48 h, then cooled to room temperature, and the solvent was removed under vacuum to obtain a crude product system. The crude NMR analysis results of the crude product system showed that no 10H-indolo[1,2-a]indole compound 1 was detected. Comparative Example 2 The difference between this comparative example and Example 1 is that Mo(CO)6 and 3,5-di-tert-butyl-o-benzoquinone are replaced by FeCl3. A method for efficiently synthesizing a 10H-indolo[1,2-a]indole compound comprises the following steps: Step 1. Under nitrogen, add 0.04 mmol FeCl3 (6.4 mg) and 2 mL mesitylene to a 10 mL Schlenk reaction tube. Seal the reaction tube and place it at 160°C for 15 min, then cool to room temperature. Step 2. Under nitrogen, 0.2 mmol of substrate S1-1 (65.0 mg) was added, the reaction tube was sealed and placed at 160°C for further reaction for 48 h, then cooled to room temperature, and the solvent was removed under vacuum to obtain a crude product system. The crude NMR analysis results of the crude product system showed that no 10H-indolo[1,2-a]indole compound 1 was detected. The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Any person skilled in the art can, without departing from the spirit and technical solution of the present invention, make many possible changes and modifications to the technical solution of the present invention using the methods and technical contents disclosed above, or modify it into an equivalent embodiment with equivalent changes. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention shall still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for efficiently synthesizing a 10H-indolo[1,2-a]indole compound, characterized in that: The following steps are involved: Step 1. Molybdenum hexacarbonyl is dissolved in mesitylene, and 3,5-di-tert-butyl-o-benzoquinone is added thereto and reacted at 150-160° C. for 15-20 minutes to prepare a mixed system; Step 2. Add the starting material S1 and PPh3 to the mixed system, react at 150-160°C for 48-60h, cool and remove the solvent, and purify to obtain a 10H-indolo[1,2-a]indole compound.

2. A method for efficiently synthesizing 10H-indolo[1,2-a]indole compounds according to claim 1, characterized in that, The molecular structure of the starting material S1 in step 1 is as follows: Wherein R is C6H5 or 4-BrC6H4.

3. A method for efficiently synthesizing 10H-indolo[1,2-a]indole compounds according to claim 1, characterized in that, The molar ratio of the molybdenum hexacarbonyl, 3,5-di-tert-butyl-o-benzoquinone and the starting material S1 is (0.15-0.2):(0.15-0.2):1.

0.

4. A method for efficiently synthesizing a 10H-indolo[1,2-a]indole compound according to claim 1, characterized in that: The molecular structural formula of the 10H-indolo[1,2-a]indole compound in step 2 is any one of the following:

5. A 10H-indolo[1,2-a]indole compound synthesized according to the method according to any one of claims 1 to 4.

6. Use of the 10H-indolo[1,2-a]indole compound according to claim 5 in drug synthesis.

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