3-keto carbonyl 1, 4-dihydroquinoline and preparation method thereof

Abstract

The invention provides 3-keto carbonyl 1, 4-dihydroquinoline and a preparation method thereof.According to the method, a starting material with both carbonyl and alkynyl is ingeniously used, under catalytic mediation of metal molybdenum, carbonyl-alkyne metathesis reaction in molecules is carried out, then hydrogen transfer is carried out, and the 3-keto carbonyl 1, 4-dihydroquinoline is smoothly converted into 1, 4-dihydroquinoline with the 3-position containing a keto carbonyl substituent, and the 3-keto carbonyl 1, 4-dihydroquinoline with the 3-position containing a keto carbonyl substituent is obtained. The invention discloses a 2, 4-dihydroquinoline product and belongs to the field of organic synthesis. According to the preparation method, the reaction rate is high, operation steps are simple and visual, the synthesis efficiency of dihydroquinoline can be remarkably improved, meanwhile, reaction reagents used in the preparation method are widely available and economical in cost, and the preparation method is suitable for industrial production. The method has the characteristics of efficient conversion, high-purity product output, minimum environmental influence, high reaction selectivity, wide substrate applicability and high yield, and provides great convenience and cost advantages for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to 3-ketocarbonyl 1,4-dihydroquinoline and a preparation method thereof. Background Art

[0002] 1,4-dihydroquinoline is a heterocyclic compound with two hydrogen atoms located at the 1st and 4th positions in the quinoline ring. With its unique chemical structure and diverse biological activities, it has shown excellent application potential in many fields. In the field of drug development, 1,4-dihydroquinoline substances, as key components of pharmacophores or structural units, have opened up a broad path for the design and synthesis of new drugs; in the field of organic synthesis, 1,4-dihydroquinoline substances, as important intermediates, can participate in a variety of organic reactions and are widely used in the construction and modification of complex organic molecules. In the prior art, 1,4-dihydroquinoline can be prepared by a variety of methods. For example, a study used a palladium-catalyzed tandem reaction to generate 1,4-dihydroquinoline containing a ketocarbonyl substituent at the 3-position by 6-endo-trig cyclization of o-iodo-N-alkenylaniline and p-toluenesulfonyl hydrazide. The synthetic reaction formula is as follows: For example, invention patent CN111170940A reports that 1,4-dihydroquinoline containing a ketocarbonyl substituent at the 3-position can be prepared by using quinoline as a raw material in a tetrahydrofuran solvent by adding a Grignard reagent and trifluoroacetic anhydride to react, and further confirms that this type of compound has significant anti-tumor activity. The synthetic reaction formula is as follows. The reported methods all face severe challenges when attempting large-scale industrial production, the main problem being high costs or overly harsh reaction conditions. For example, when p-toluenesulfonyl hydrazide is used as a substrate, not only a large amount of excess tert-butyl lithium (6 equivalents) is required in the reaction process, but also expensive tetrakistriphenylphosphine palladium is required as a catalyst, which not only leads to serious waste of raw materials, but also significantly increases production costs; in addition, the diazo compounds produced in the process are potentially explosive, which will bring safety hazards to industrial production. For example, the method described in the invention patent CN111170940A uses boron trifluoride ether, which is extremely sensitive to moisture, as a catalyst and a Grignard reagent, making the reaction operation complicated and risky, and must be carried out under strict anhydrous and inert gas protection conditions; at the same time, the subsequent treatment of the method is also quite complicated, including the difficulty of wastewater treatment, the cumbersome separation and purification of products, and potential safety risks. More noteworthy is that this type of product is limited to 3-substituted alkyl ketone compounds, and the product types are subject to certain restrictions. In summary, these methods have obvious limitations and challenges when applied to large-scale production. In recent years, with the increasing popularity of green chemistry and sustainable chemistry, more and more researchers have begun to pay attention to how to reduce the emission of harmful substances, improve resource utilization efficiency, and develop recyclable or bio-based catalysts during the synthesis process. The present invention proposes a 3-ketocarbonyl 1,4-dihydroquinoline and a preparation method thereof, which not only overcomes many problems existing in traditional synthesis methods, but also provides strong support for the wide application of dihydroquinoline compounds and promotes the development of related industries in a green and sustainable direction. Summary of the invention

[0003] Technical problems to be solved: In view of the above technical problems, the purpose of the present invention is to provide a 3-ketocarbonyl 1,4-dihydroquinoline and a preparation method thereof, which cleverly uses starting materials with both carbonyl and alkynyl groups, and under the catalytic mediation of metal molybdenum, a carbonyl-alkyne metathesis reaction occurs within the molecule, and then undergoes a hydrogen transfer step to smoothly convert it into a 1,4-dihydroquinoline product containing a ketocarbonyl substituent at the 3-position, belonging to the field of organic synthesis. The preparation method of the present invention not only has a fast reaction rate, but also has precise and simple operation steps, which can significantly improve the synthesis efficiency of dihydroquinoline. At the same time, the reaction reagents used in the preparation method are widely available and cost-effective, and have the characteristics of efficient conversion, high-purity product output, minimized environmental impact, high reaction selectivity, wide substrate applicability, and high yield, which provides great convenience and cost advantages for industrial large-scale production.

[0004] Technical solution: A 3-ketocarbonyl 1,4-dihydroquinoline, wherein the structural molecular formula of the 3-ketocarbonyl 1,4-dihydroquinoline is any one of the following. Furthermore, a method for preparing 3-ketocarbonyl 1,4-dihydroquinoline comprises the following steps: Step 1. Activating molybdenum hexacarbonyl to obtain a high-valent molybdenum catalyst; Step 2. Under the catalysis of a high-valent molybdenum catalyst, an aromatic compound containing a carbonyl group and an alkynyl group undergoes an intramolecular carbonyl-alkyne metathesis reaction to obtain 3-ketocarbonyl 1,4-dihydroquinoline. The synthetic reaction formula is as follows: The reaction mechanism is as follows: ① Under heating conditions, hexacarbonyl molybdenum and kun undergo activation reaction to generate catalyst intermediate M-1; ② The catalyst intermediate M-1 coordinates with the carbonyl oxygen of the aromatic compound containing carbonyl and alkynyl groups to form the reaction intermediate Int-1, making the carbonyl carbon center more electron-deficient and becoming a site for nucleophilic addition of the alkyne part; ③ The alkyne part of the aromatic compound containing carbonyl and alkynyl groups undergoes a [2+2] cycloaddition reaction with the carbonyl part to generate the intermediate Int-2, which serves as the key to constructing the skeleton of the target product; ④ The intermediate Int-2 undergoes further ring-opening reaction to generate the intermediate Int-3, which may be accompanied by hydrogen transfer to generate the intermediate Int-4; ⑤The catalyst dissociates from the intermediate Int-4 to produce 3-ketocarbonyl 1,4-dihydroquinoline. Furthermore, the specific method for activating molybdenum hexacarbonyl in step 1 is: dissolving molybdenum hexacarbonyl and 3,5-di-tert-butyl-o-benzoquinone in solvent A, reacting at 140-160° C. for 15-30 minutes, and cooling to room temperature to prepare a high-valent molybdenum catalyst. Furthermore, the molar ratio of the molybdenum hexacarbonyl to 3,5-di-tert-butyl-o-benzoquinone is 0.1:(0.1-0.12). Furthermore, the solvent A includes but is not limited to mesitylene, toluene, and o-xylene. Furthermore, the structural formula of the aromatic compound containing carbonyl and alkynyl groups in step 2 is as follows: Wherein R includes but is not limited to phenyl, 4-methylphenyl, 4-bromophenyl, and cyclopropyl. Furthermore, the molar mass of the aromatic compound containing carbonyl and alkynyl groups in step 2 is 5-10 times the molar mass of molybdenum hexacarbonyl. Furthermore, the reaction conditions of the carbonyl-alkyne metathesis reaction in step 2 are a reaction temperature of 140-160° C. and a reaction time of 48-72 h. Beneficial effects: 1. The present invention adopts an aromatic compound containing a carbonyl group and an alkynyl group as a reaction substrate, and an intramolecular carbonyl-alkyne metathesis reaction and a hydrogen transfer process occur under the catalytic conditions of metal molybdenum. An intramolecular cyclization reaction strategy is used to prepare 3-ketocarbonyl 1,4-dihydroquinoline, which can efficiently guide the formation of the target product, and no additional by-products are generated during the whole process. It is highly selective, not only improving the purity and yield of the product, but also reducing the generation of waste from the source. From the dual perspectives of atomic economy and environmental friendliness, it sets a new benchmark for the development of green chemistry. 2. The present invention utilizes high-valent molybdenum after activation with molybdenum hexacarbonyl as a Lewis acid catalyst, which significantly reduces the amount of catalyst used, making the reaction operation simpler and more environmentally friendly, and also achieves green production without additional by-products, while greatly reducing production costs and effectively avoiding the generation of potential high-risk diazo compounds, thereby ensuring the safety of industrial production at the source and providing more reliable and robust protection for large-scale production. 3. The preparation method of dihydroquinoline compounds in the present invention can not only improve the economy and environmental protection of the reaction, but also provide a more feasible option for industrial production. In addition, it successfully expands the substrate range to the synthesis of 3-substituted aromatic ketone 1,4-dihydroquinoline, providing a new method and path for the synthesis of such compounds, and providing a wider and more flexible option for subsequent research and application. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is the H NMR spectrum of the target product 1 in Example 1; Figure 2 is the NMR carbon spectrum of the target product 1 in Example 1; Figure 3 is the H NMR spectrum of the target product 2 in Example 2; Figure 4 is the NMR carbon spectrum of the target product 2 in Example 2; Figure 5 is a single crystal structure diagram of target product 2 in Example 2; Figure 6 is the H NMR spectrum of the target product 3 in Example 3; Figure 7 is the NMR carbon spectrum of the target product 3 in Example 3; Figure 8 is the H NMR spectrum of the target product 4 in Example 4; Fig. 9 This is the NMR carbon spectrum of the target product 4 in Example 4. DETAILED DESCRIPTION The present invention will be further described below in conjunction with embodiments, which are explanations of the present invention and are not limited to the following embodiments: Example 1 A method for preparing 3-ketocarbonyl 1,4-dihydroquinoline comprises the following steps: Step 1. Under nitrogen, add 0.02 mmol Mo(CO)6 (5.3 mg), 0.02 mmol 3,5-di-tert-butyl o-benzoquinone (4.4 mg) and 2 mL mesitylene into a 10 mL Schlenk reaction tube. Seal the reaction tube and place it at 160°C for 15 min, then cool to room temperature to obtain a high-valent molybdenum catalyst. Step 2. Under nitrogen and high-valent molybdenum catalyst conditions, 0.2 mmol of substrate S1-1 (65.1 mg) was added, and its molecular structure is as follows: The reaction tube was then sealed and placed at 160° C. for 48 h, cooled to room temperature, and the solvent was removed under vacuum. The product was then purified by column chromatography (eluent: 10% ethyl acetate / petroleum ether) to obtain 56.6 mg of the target product 1 with a yield of 87%. The molecular structure is as follows. Depend on Figure 1 and Figure 2 It can be seen that the NMR data of the target product 1: 1H NMR (400MHz, CDCl3) δ = 7.49 (d, J = 7.0Hz, 1H), 7.41 (dq, J = 14.3, 7.1Hz, 1H), 7.30 (d, J = 7.6Hz, 1H), 7.26-7.18 (m, 1H), 7.15-7.09 (m, 1H), 7.04 (t, J = 7.4Hz, 1H), 6.94 (d, J = 8.1Hz, 1H), 5.5 5(s,1H),3.32(s,1H).13CNMR(100MHz,CDCl3)δ=193.4,147.6,147.0,140.2,137.5,130.6, 123.0,128.3,128.26,128.0,127.4,127.2,127.19,126.0,124.2,113.6,112.7,41.6,39.4. Example 2 A method for preparing 3-ketocarbonyl 1,4-dihydroquinoline comprises the following steps: Step 1. Under nitrogen, add 0.02 mmol Mo(CO)6 (5.3 mg), 0.02 mmol 3,5-di-tert-butyl o-benzoquinone (4.4 mg) and 2 mL mesitylene into a 10 mL Schlenk reaction tube. Seal the reaction tube and place it at 160°C for 15 min, then cool to room temperature to obtain a high-valent molybdenum catalyst. Step 2. Under nitrogen and high-valent molybdenum catalyst conditions, 0.2 mmol of substrate S1-2 (67.9 mg) was added, and its molecular structure is as follows: The reaction tube was then sealed and placed at 160°C for 48 hours, cooled to room temperature, and the solvent was removed under vacuum. The product was then purified by column chromatography (eluent: 10% ethyl acetate / petroleum ether) to obtain 59.8 mg of the target product 2 with a yield of 88%. The molecular structure is as follows. Depend on Figure 3 and Figure 4 It can be seen that the NMR data of the target product 2: 1H NMR (400MHz, CDCl3) δ = 7.41 (d, J = 8.0 Hz, 1H), 7.32-7.25 (m, 1H), 7.20 (ddd, J = 8.0, 6.3, 3.0 Hz, 2H), 7.13-7.08 (m, 1H), 7.03 (td, J = 7.5, 1.0 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 5.54 (s, 1H), 3.32 (s,1H),2.39(s,1H).13CNMR(100MHz,CDCl3)δ=193.4,147.7,146.6,140.3,137.6,137.4,130 .6,128.7,128.5,128.3,127.5,127.2,127.16,126.0,124.1,113.6,112.6,41.7,39.4,21.4. based on Figure 5 The single crystal structure of the target product 2 was obtained, and the crystal data of the target product 2 was obtained, as shown in Table 1. Table 1 Crystal data of target product 2 Example 3 A method for preparing 3-ketocarbonyl 1,4-dihydroquinoline comprises the following steps: Step 1. Under nitrogen, add 0.02 mmol Mo(CO)6 (5.3 mg), 0.02 mmol 3,5-di-tert-butyl o-benzoquinone (4.4 mg) and 2 mL mesitylene into a 10 mL Schlenk reaction tube. Seal the reaction tube and place it at 160°C for 15 min, then cool to room temperature to obtain a high-valent molybdenum catalyst. Step 2. Under nitrogen and high-valent molybdenum catalyst conditions, 0.2 mmol of substrate S1-3 (80.9 mg) was added, and its molecular structure is as follows: The reaction tube was then sealed and placed at 160°C for 48 hours, cooled to room temperature, and the solvent was removed under vacuum. The product was then purified by column chromatography (eluent: 10% ethyl acetate / petroleum ether) to obtain 68.7 mg of the target product 3 with a yield of 85%. The molecular structure is as follows. Depend on Figure 6 and Figure 7 It can be seen that the NMR data of the target product 3 is: 1 H NMR (400MHz, CDCl3) δ = 7.52 (d, J = 8.2Hz, 1H), 7.36 (d, J = 8.2Hz, 1H), 7.24 (dt, J = 22.9, 7.4Hz, 2 H),7.12(t,J=7.1Hz,1H),7.08-7.01(m,1H),6.95(d,J=8.4Hz,1H),5.51(s,1H),3.35(s,1H). 13 C NMR (100MHz, CDCl3)δ=192.1,147.5,146.9,139.0,137.3,131.2,130.6,1 29.9,128.3,127.4,127.3,127.1,126.1,124.4,113.4,112.8,41.6,39.5. Example 4 A method for preparing 3-ketocarbonyl 1,4-dihydroquinoline comprises the following steps: Step 1. Under nitrogen, add 0.02 mmol Mo(CO)6 (5.3 mg), 0.02 mmol 3,5-di-tert-butyl o-benzoquinone (4.4 mg) and 2 mL mesitylene into a 10 mL Schlenk reaction tube. Seal the reaction tube and place it at 160°C for 15 min, then cool to room temperature to obtain a high-valent molybdenum catalyst. Step 2. Under nitrogen and high-valent molybdenum catalyst conditions, 0.2 mmol of substrate S1-4 (57.9 mg) was added, and its molecular structure is as follows: The reaction tube was sealed and placed at 160°C for 48 hours, cooled to room temperature, and the solvent was removed under vacuum. The product was then purified by column chromatography (eluent: 10% ethyl acetate / petroleum ether) to obtain 46.3 mg of the target product 4 with a yield of 80%. The molecular structure is as follows. Depend on Figure 8 and Fig. 9 It can be seen that the NMR data of the target product 4 is: 1H NMR (400MHz, CDCl3) δ = 7.57 (s, 1H), 7.27-7.16 (m, 3H), 7.12-7.06 (m, 1H), 6.99 (t, J = 7.4Hz, 1H), 6.93 (d,J=8.1Hz,1H),5.36(s,1H),3.43(s,1H),2.20–2.11(m,1H),1.05–0.91(m,1H),0.79–0.67(m,1H). 13 C NMR (100MHz, CDCl3) δ=195.5,147.7,142.5,137.8,130.4,128.3,127.3,127.27,127.1,126.0,123.8,114.1,112.5,41.9,39.3,15.2,9.4,9.1. Comparative Example 1 The difference between this comparative example and Example 1 is that molybdenum hexacarbonyl is replaced by ferric chloride. A method for preparing 3-ketocarbonyl 1,4-dihydroquinoline comprises the following steps: Step 1. Under nitrogen, add 0.02 mmol FeCl3 (3.2 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 conditions, 0.2 mmol of substrate S1-1 (65.1 mg) was added, and its molecular structure is as follows: The reaction tube was then sealed and placed at 160° C. for 48 h, cooled to room temperature, and the solvent was removed under vacuum. The reaction system was subjected to crude NMR analysis, and the results showed that no target product 1 was detected. Comparative Example 2 The difference between this comparative example and Example 1 is that molybdenum hexacarbonyl is replaced by boron trifluoride etherate. A method for preparing 3-ketocarbonyl 1,4-dihydroquinoline comprises the following steps: Step 1. Under nitrogen, add 0.02 mmol of boron trifluoride etherate (2.8 mg) and 2 mL of mesitylene into 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 conditions, 0.2 mmol of substrate S1-1 (65.1 mg) was added, and its molecular structure is as follows: The reaction tube was then sealed and placed at 160° C. for 48 h, cooled to room temperature, and the solvent was removed under vacuum. The reaction system was subjected to crude NMR analysis, and the results showed that no target product 1 was detected. The above is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any technician familiar with the art can make many possible changes and modifications to the technical solution of the present invention by using the above disclosed methods and technical contents without departing from the spirit and technical solution of the present invention, or modify it into an equivalent embodiment of equivalent changes. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the scope of protection of the technical solution of the present invention.

Claims

1. A 3-ketocarbonyl 1,4-dihydroquinoline, characterized in that: The structural molecular formula of the 3-ketocarbonyl 1,4-dihydroquinoline is any one of the following.

2. The method for preparing 3-ketocarbonyl 1,4-dihydroquinoline according to claim 1, characterized in that: The following steps are involved: Step 1. Activating molybdenum hexacarbonyl to obtain a high-valent molybdenum catalyst; Step 2. Under the catalysis of a high-valent molybdenum catalyst, an aromatic compound containing a carbonyl group and an alkynyl group undergoes an intramolecular carbonyl-alkyne metathesis reaction to produce 3-ketocarbonyl 1,4-dihydroquinoline.

3. The method for preparing 3-ketocarbonyl 1,4-dihydroquinoline according to claim 2, characterized in that: The specific method for activating molybdenum hexacarbonyl in step 1 is: dissolving molybdenum hexacarbonyl and 3,5-di-tert-butyl-o-benzoquinone in solvent A, reacting at 140-160° C. for 15-30 minutes, and cooling to room temperature to prepare a high-valent molybdenum catalyst.

4. The method for preparing 3-ketocarbonyl 1,4-dihydroquinoline according to claim 3, characterized in that: The solvent A includes but is not limited to mesitylene, toluene, and o-xylene.

5. The method for preparing 3-ketocarbonyl 1,4-dihydroquinoline according to claim 3, characterized in that: The molar ratio of the molybdenum hexacarbonyl to 3,5-di-tert-butyl-o-benzoquinone is 0.1:(0.1-0.12).

6. The method for preparing 3-ketocarbonyl 1,4-dihydroquinoline according to claim 2, characterized in that: The structural formula of the aromatic compound containing carbonyl and alkynyl in step 2 is as follows: Wherein R includes but is not limited to phenyl, 4-methylphenyl, 4-bromophenyl, and cyclopropyl.

7. The method for preparing 3-ketocarbonyl 1,4-dihydroquinoline according to claim 2, characterized in that: The molar mass of the aromatic compound containing carbonyl and alkynyl in step 2 is 5-10 times the molar mass of molybdenum hexacarbonyl.

8. The method for preparing 3-ketocarbonyl 1,4-dihydroquinoline according to claim 2, characterized in that: The reaction conditions of the carbonyl-alkyne metathesis reaction in step 2 are a reaction temperature of 140-160° C. and a reaction time of 48-72 h.

Images