CN115650914A - Preparation method of indenoquinoline derivative - Google Patents

Abstract

This patent application discloses a preparation method of indenoquinoline derivatives. Based on the strategy of orderly and multiple carbon-hydrogen bond activation, the method is based on the orderly [3+2] and [4+2] cyclization reactions of Schiff bases and propargyl alcohols catalyzed by metal catalysts to obtain indenoquinolines. derivative. The transformation has high efficiency and good regioselectivity. At the same time, the method only uses simple and readily available Schiff bases as reaction substrates, has good atom economy, and the by-product is water. More importantly, the reaction synthesizes indenoquinoline derivatives from two simple raw materials in one step. In the reaction mode, the C-H activation of the bisaryl group and the three carbon-hydrogen bond activation processes of the C-H bond activation of the imine occur. One-step synthesis of complex fused heterocyclic rings, this indenoquinoline skeleton widely exists in natural products, and exhibits good antitumor activity.

Description

A kind of preparation method of indenoquinoline derivative

technical field

This patent application relates to the technical field of organic compound synthesis, more specifically, to a preparation method of indenoquinoline derivatives.

Background technique

Nitrogen-containing heterocyclic or condensed ring compounds such as quinoline, indole, indenoquinoline and other cyclic compounds are important alkaloid skeletons and widely exist in many natural products and pharmacologically active compounds. Classical fused heterocycle synthesis often requires multi-step synthesis and relatively harsh reaction conditions, which also lead to poor functional group compatibility and relatively narrow substrate scope for these transformations.

The currently clinically used targeted anticancer drug inhibitors with high efficiency and low toxicity mainly include camptothecin compounds and non-camptothecin compounds. Camptothecin is a class of five-membered ring alkaloids containing a quinoline skeleton. Most of the topoisomerase inhibitors show selective inhibitory effect on topo I and topo II, and few molecules can inhibit simultaneously, and some indenoquinoline derivatives have been found to be topo I and topo II's targeted drug can simultaneously inhibit these two topoisomerases. And there are many methods for separating and extracting indenoquinoline derivatives of camptothecin (camptothecin) class, but there are certain limitations in the method for separating and extracting, and the quantity that they exist in nature can not meet people's needs, so the high-efficiency module The synthesis of this kind of indenoquinoline derivatives has good application value.

缩合的方法，需使用邻氨基苯甲醛和茚酮化合物缩合而成，但底物范围受限，部分底物需经过硝化反应和还原硝基反应等预先合成，步骤繁琐且使用大量的强酸，严重危害环境。The traditional synthesis of indenoquinoline derivatives is mainly through

The condensation method needs to be formed by condensation of o-aminobenzaldehyde and indanone compound, but the range of substrates is limited, and some substrates need to be pre-synthesized through nitration reaction and reduction nitro reaction. The steps are cumbersome and a large amount of strong acid is used. Serious Harmful to the environment.

With the rapid development of transition metal-catalyzed reactions, the strategy of constructing C-C bonds and C-X bonds directly through metal-catalyzed C-H activation in one step is atom-economical and environmentally friendly, which is more in line with the development of modern chemistry. The researchers discovered that the use of 2-alkynyl halobenzenes and primary amines was coupled under the action of zero-valent palladium to obtain 2-alkynyl aniline compounds, and then another molecule of 2-alkynyl halobenzenes was coupled under the action of zero-valent palladium. Oxidative addition occurs, the alkyne insertion of the in situ generated 2-alkynylaniline, the generated alkenyl palladium species then inserts the carbon-carbon triple bond in the molecule, and finally the carbon-nitrogen coupling generates the indenoquinoline derivative (Chem. Asinn J., 2012, 7, 1691-1696.). However, this type of reaction requires pre-synthesis of more complex substrates, and the scope of substrates is limited.

It can be seen that it is still a major challenge to design new substrates and coupling molecules to construct complex molecules of indenoquinoline derivatives simply and quickly.

Patent application content

In order to overcome at least one problem existing in the prior art, this patent application provides a preparation method of indenoquinoline derivatives. The preparation method in this patent application uses multiple dehydrogenation strategies. Under the promotion of a trivalent rhodium metal catalyst, the Schiff base and phenylpropargyl alcohol undergo alkyne cycloaddition and intramolecular Friedel-Crafts reaction to realize In order to prepare various indenoquinoline derivatives with high efficiency and high selectivity.

In order to solve the problems of the technologies described above, the technical solution adopted in this patent application is:

A kind of preparation method of indenoquinoline derivative, it is characterized in that: in inert solvent, and under the effect of metal catalyst, Schiff base compound (formula II) is reacted with propargyl alcohol compound (formula III), Obtain indenoquinoline derivatives (formula I), and the reaction equation is as follows:

Wherein Ar is benzene and naphthalene containing substituents such as trifluoromethyl, halogen, ether, etc., ^R is alkyl, ester group, ether, etc., R is phenyl containing ether, ester group substitution, thiophene ^.

Compared with prior art, the beneficial effect of this patent application is:

The preparation method of indenoquinoline derivatives provided by this patent application has the characteristics of easy availability of raw materials, high atom economy and step economy. Based on the strategy of multiple dehydrogenation, the Schiff base and propargyl alcohol catalyzed by a metal catalyst The cycloaddition and subsequent intramolecular Friedel-Crafts reaction synthesized the target product in one step, and the molecular skeleton showed good antitumor activity.

Description of drawings

Fig. 1 is the proton nuclear magnetic resonance spectrogram of compound 1a prepared in Example 1 of the present patent application;

Fig. 2 is the carbon nuclear magnetic resonance spectrogram of compound 1a prepared in Example 1 of the present patent application;

Figure 3 is the NMR fluorine spectrum of compound 1a prepared in Example 1 of the present patent application;

Figure 4 is the H NMR spectrum of compound 1b prepared in Example 2 of the present patent application;

Figure 5 is the carbon nuclear magnetic resonance spectrum of compound 1b prepared in Example 2 of the present patent application;

Figure 6 is the H NMR spectrum of compound 1c prepared in Example 3 of the present patent application;

Figure 7 is the carbon nuclear magnetic resonance spectrum of compound 1c prepared in Example 3 of the present patent application;

Figure 8 is the NMR fluorine spectrum of compound 1c prepared in Example 3 of the present patent application;

Figure 9 is the proton nuclear magnetic resonance spectrum of compound 1d prepared in Example 4 of the present patent application;

Figure 10 is the carbon nuclear magnetic resonance spectrum of compound 1d prepared in Example 4 of the present patent application;

Figure 11 is the NMR fluorine spectrum of compound 1d prepared in Example 4 of the present patent application;

Figure 12 is the proton nuclear magnetic resonance spectrum of compound 1e prepared in Example 5 of the present patent application;

Figure 13 is the carbon nuclear magnetic resonance spectrum of compound 1e prepared in Example 5 of the present patent application;

Figure 14 is the NMR fluorine spectrum of compound 1e prepared in Example 5 of the present patent application;

Figure 15 is the H NMR spectrum of compound 1f prepared in Example 6 of the present patent application;

Figure 16 is the carbon nuclear magnetic resonance spectrum of compound 1f prepared in Example 6 of the present patent application;

Figure 17 is the NMR fluorine spectrum of compound 1f prepared in Example 6 of the present patent application;

Figure 18 is the H NMR spectrum of compound 1g prepared in Example 7 of the present patent application;

Figure 19 is the H NMR spectrum of compound 1g prepared in Example 7 of the present patent application;

Figure 20 is the NMR fluorine spectrum of compound 1g prepared in Example 7 of this patent application;

Figure 21 is the H NMR spectrum of compound 1h prepared in Example 8 of the present patent application;

Figure 22 is the carbon nuclear magnetic resonance spectrum of compound 1h prepared in Example 8 of the present patent application;

Figure 23 is the NMR fluorine spectrum of compound 1h prepared in Example 8 of the present patent application;

Figure 24 is the proton nuclear magnetic resonance spectrum of compound 1i prepared in Example 9 of the present patent application;

Figure 25 is the carbon nuclear magnetic resonance spectrum of compound 1i prepared in Example 9 of the present patent application;

Figure 26 is the H NMR spectrum of compound 1j prepared in Example 10 of the present patent application;

Figure 27 is the carbon nuclear magnetic resonance spectrum of compound 1j prepared in Example 10 of the present patent application.

Detailed ways

Embodiments of the present patent application will be described in detail below in conjunction with examples, but those skilled in the art will understand that the following examples are only used to illustrate the present patent application, and should not be considered as limiting the scope of the present patent application. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.

It should be noted:

In this patent application, unless otherwise specified, all the implementation modes and preferred implementation methods mentioned herein can be combined with each other to form new technical solutions.

In this patent application, unless otherwise specified, each reaction or operation step can be carried out sequentially or in sequence. Preferably, the reaction processes herein are performed sequentially.

Unless otherwise specified, professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to the content described can also be applied to this patent application.

A kind of preparation method of indenoquinoline derivative, it is characterized in that: in inert solvent, and under the effect of metal catalyst, Schiff base compound (formula II) is reacted with propargyl alcohol compound (formula III), Obtain indenoquinoline derivative (formula I), and its reaction equation is as follows:

Wherein Ar is benzene and naphthalene containing substituents such as trifluoromethyl, halogen, ether, etc., ^R is alkyl, ester group, ether, etc., R is phenyl containing ether, ester group substitution, thiophene ^.

The preparation method of this patent application uses the Schiff base formed by the dehydration condensation of popular chemicals aromatic aldehyde and aromatic amine to undergo cycloaddition and intramolecular Friedel-Crafts reaction under transition metal catalysis to obtain indenoquinoline The derivatives have good atom economy and step economy, and at the same time solve the problem of regioselectivity generated by migratory insertion of alkynes in transition metal-catalyzed processes. This reaction activates the three hydrogens on the Schiff base, and constructs complex condensed heterocyclic indenoquinoline derivatives in the next step of phenylpropargyl alcohol coupling.

In some embodiments, the inert solvent is toluene, tetrahydrofuran, 1,4-dioxane, N,N'-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, 1, One or more of 2-dichloroethane, ethanol, and trifluoroethanol.

In some preferred embodiments, the metal catalyst is: pentamethylcyclopentadiene rhodium chloride dimer, bis(4-methylisopropylphenyl) ruthenium dichloride, pentamethylcyclopentadiene Any one or more of iridium chloride dimer and triacetonitrile-pentamethylcyclopentadienyl rhodium chloride dimer.

In some preferred embodiments, the halogen atom grabbing agent is one of silver hexafluoroantimonate, silver bistrifluoromethanesulfonimide or a combination thereof.

In some preferred embodiments, the oxidizing agent is one or more of silver acetate, silver carbonate, copper acetate, and silver oxide.

In some preferred embodiments, the amount of the metal catalyst is 2 mol% of the amount of the Schiff base compound (Formula II).

In some preferred embodiments, the amount of the halogen atom scavenger is 5 mol% of the amount of the Schiff base compound (Formula II).

In some preferred embodiments, the reaction temperature is 80°C-120°C.

In some preferred embodiments, the reaction is performed for 12-24 hours.

In some preferred embodiments, the preparation method of the above-mentioned indenoquinoline derivatives includes the following specific steps:

S1: In the reactor, in the air, sequentially add 2.5mg of pentamethylcyclopentadiene rhodium chloride dimer, 3.9mg of silver trifluoromethanesulfonimide, 39.8mg of silver acetate, 1.0mL of solvent dichloro Ethane, 55.8 mg of Schiff base, 47.2 mg of phenylpropargyl alcohol;

S2: Reacting the reaction at a temperature of 100° C. for 12 hours;

S3: After the reaction, the above mixture is separated by column chromatography to obtain the target compound.

Next, the preparation method of indenoquinoline derivatives of this patent application will be described in detail with specific examples.

Example 1 Preparation of 8-methoxy-10,10-dimethyl-11-phenyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline (1a)

Under an atmosphere of atmospheric pressure air, N-(4-methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)toluidine 2a (27.9mg, 0.10mmol ), phenylpropargyl alcohol 3a (16.0mg, 0.10mmol), trivalent rhodium catalyst [Cp*RhCl ₂ ] ₂ (2.5mg, 0.004mmol), silver trifluoromethanesulfonimide (3.9mg, 0.01mmol) , silver acetate (33.4mg, 0.20mmol), dichloroethane (DCE, 1.0mL), react at a temperature of 100°C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, and then concentrated to obtain a crude product. The crude product was separated by thin chromatography on a prepared silica gel plate, the selected developing solvent or eluent was a mixed solvent of sherwood oil and ethyl acetate, and the volume ratio of sherwood oil and ethyl acetate was 20:1, and the result was 78 The product 8-methoxy-10,10-dimethyl-11-phenyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline (1a) was obtained in % yield . The chemical reaction equation corresponding to this embodiment is as follows:

The H NMR spectrum, C NMR spectrum and F NMR spectrum of the compound prepared in Example 1 are shown in Figure 1, Figure 2 and Figure 3. It can be seen from Figure 1: ¹ H NMR (400MHz, CDCl ₃ ) δ7.98 (d, J=7.6Hz, 1H), 7.67 (d, J=8.4Hz, 1H), 7.54-7.47 (m, 4H) ,7.36(d,J=6.4Hz,2H),6.97(d,J=2.8Hz,1H),6.92(s,1H),6.88(dd,J=2.8Hz,8.4Hz,1H),3.86(s ,3H), 1.43(s,6H). Molecular hydrogen spectrum peaks can correspond to the target product one by one, and the number is reasonable. It can be seen from Figure 2 that: ¹³ C NMR (100MHz, CDCl ₃ ) δ161.1, 160.5, 146.6, 145.3, 140.0, 136.9, 136.6, 134.4, 134.3, 131.9 (q, J=32.0Hz), 130.9, 129.0, 128.8, 128.5, 128.3, 124.2 (q, J = 270.0Hz), 123.5 (q, J = 4.0Hz), 120.8, 166.6 (q, J = 4.0Hz), 112, 8, 111.4, 55.5, 36.6, 31.2. The peaks of the molecular carbon spectrum can correspond to the target product one by one, and the number is reasonable. It can be seen from Fig. 3 that: ¹⁹ F NMR (100 MHz, CDCl ₃ ) δ-62.2. Combined with the results of the above proton NMR spectrum, carbon spectrum, and fluorine spectrum, it can be seen that the product obtained in Example 1 is 8-methoxyl-10,10-dimethyl-11-phenyl-2-(trifluoromethyl )-10H-indeno[1,2-b]quinoline (1a).

In this example, the indenoquinoline derivative 8-methoxy-10,10-dimethyl-11-phenyl-2-(trifluoromethyl)-10H-indeno[1,2-b ] The preparation method of quinoline (1a) has few steps, is easy to operate, and has a very wide range of application to substrates, and is also easy to follow-up for further transformation. The invention of this application has good atom economy, and the by-product is water, and has efficient step economy and atom economy.

The chemical conversion in this example is compatible with trifluoromethyl, which is widely used in the fields of materials and medicine.

Example 2 Preparation of 2-bromo-8-methoxy-10,10-dimethyl-11-phenyl-10H-indeno[1,2-b]quinoline (1b)

Under an atmosphere of atmospheric pressure air, 1-(4-bromophenyl)-N-(4-methoxyphenyl)toluidine 2b (28.9mg, 0.10mmol), phenylpropargyl Alcohol 3a (16.0mg, 0.10mmol), trivalent rhodium catalyst [Cp*RhCl ₂ ] ₂ (2.5mg, 0.004mmol), silver trifluoromethanesulfonimide (3.9mg, 0.01mmol), silver acetate (33.4mg , 0.20mmol), dichloroethane (DCE, 1.0mL), react at a temperature of 100°C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, and then concentrated to obtain a crude product. The crude product was separated by thin chromatography on a prepared silica gel plate, the selected developing solvent or eluent was a mixed solvent of sherwood oil and ethyl acetate, and the volume ratio of sherwood oil and ethyl acetate was 20:1, with 63% The product 2-bromo-8-methoxy-10,10-dimethyl-11-phenyl-10H-indeno[1,2-b]quinoline (1b) was obtained in good yield. The chemical reaction equation corresponding to this embodiment is as follows:

The H NMR and C NMR spectra of the compound prepared in Example 2 are shown in Figure 4 and Figure 5 . It can be seen from Figure 4: ¹ H NMR (400MHz, CDCl ₃ ) δ7.75 (d, J=8.0Hz, 1H), 7.64 (d, J=8.4Hz, 1H), 7.52-7.45 (m, 3H) ,7.38(dd,J=1.6Hz,8.0Hz,1H),7.34(dd,J=1.6Hz,8.0Hz,2H),6.95(d,J=2.8Hz,1H),6.86(dd,J=2.4 Hz, 8.4Hz, 1H), 6.83(d, J=1.6Hz, 1H), 3.85(s, 3H), 1.41(s, 6H). Molecular hydrogen spectrum peaks can correspond to the target product one by one, and the number is reasonable. It can be seen from Figure 5 that: ¹³ C NMR (100MHz, CDCl ₃ ) δ161.3, 160.2, 148.0, 145.1, 139.8, 136.9, 134.6, 134.0, 132.1, 131.8, 129.1, 129.0, 128.5, 128.2, 124.4, 123.4, 122.1, 112.8, 111.3, 55.5, 36.6, 31.2. The peaks of the molecular carbon spectrum can correspond to the target product one by one, and the number is reasonable. Combined with the results of the above proton nuclear magnetic spectrum and carbon spectrum, it can be seen that the product obtained in Example 2 is 2-bromo-8-methoxy-10,10-dimethyl-11-phenyl-10H-indeno[1 ,2-b] Quinoline (1b).

In the present embodiment, using multiple dehydrogenation strategies, under the promotion of a trivalent rhodium metal catalyst, Schiff base 1-(4-bromophenyl)-N-(4-methoxyphenyl)toluidine 2b and phenyl Propargyl alcohol 3a undergoes alkyne cycloaddition and intramolecular Friedel-Crafts reaction to achieve high-efficiency (63% yield) and high-selectivity preparation of indenoquinoline derivatives. The reaction in this embodiment only needs to be reacted for 12 hours at 100° C. under atmospheric pressure air atmosphere, then cooled, and then carry out a series of follow-up treatments to obtain the final target product compound with a higher yield (63%): 2-Bromo-8-methoxy-10,10-dimethyl-11-phenyl-10H-indeno[1,2-b]quinoline (1b).

Therefore, the preparation method of indenoquinoline derivatives in this example is a green and efficient synthesis method. This method does not require complex pre-synthesis of some substrates, and does not require cumbersome synthesis steps. It does not need to use a large amount of reagents that seriously endanger the environment such as strong acids or bases in the reaction. Therefore, it is environmentally friendly and safe. After one-step synthesis, it can be obtained efficiently. product. Efficient synthesis of indenoquinoline derivative compound 2-bromo-8-methoxy-10,10-dimethyl-11-phenyl-10H-indeno[1,2-b under milder reaction conditions ] quinoline (1b). All the raw materials in the reaction are cheap and easy to obtain, the method is simple and easy to operate, and the operation is safe, so it has potential practical value.

The chemical transformation of this application contains easily transformable functional group bromine, which provides a platform for more complex molecular construction.

Example 3 8-(tert-butyl)-10,10-dimethyl-11-phenyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline (1c) preparation

Under an atmosphere of atmospheric pressure air, N-(4-(tert-butyl)phenyl)-1-(4-(trifluoromethyl)phenyl)toluidine 2c (30.5mg, 0.10mmol), phenyl propargyl alcohol 3a (16.0mg, 0.10mmol), trivalent rhodium catalyst [Cp*RhCl ₂ ] ₂ (2.5mg, 0.004mmol), silver trifluoromethanesulfonimide (3.9mg, 0.01 mmol), copper acetate (39.8mg, 0.20mmol), dichloroethane (DCE, 1.0mL), react at a temperature of 100°C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, and then concentrated to obtain a crude product. The crude product was separated by thin chromatography on a prepared silica gel plate, the selected developing solvent or eluent was a mixed solvent of sherwood oil and ethyl acetate, and the volume ratio of sherwood oil and ethyl acetate was 20:1, with 63% The yield of the product 8-(tert-butyl)-10,10-dimethyl-11-phenyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline ( 1c). The chemical reaction equation corresponding to this embodiment is as follows:

The H NMR spectrum, C NMR spectrum and F NMR spectrum of the compound prepared in Example 3 are shown in Figure 6, Figure 7 and Figure 8. It can be seen from Figure 6: ¹ H NMR (400MHz, CDCl ₃ ) δ7.99 (d, J=7.6Hz, 1H), 7.65 (d, J=8.4Hz, 1H), 7.55-7.53 (m, 2H) ,7.28(d,J=2.0Hz,1H),7.39-7.35(m,2H),7.15(dd,J=0.8Hz,4.8Hz,1H),7.05(s,1H),1.48(s,6H) ,1.36(s,9H). Molecular hydrogen spectrum peaks can correspond to the target product one by one, and the number is reasonable. It can be seen from Fig. 7 that: ¹³ C NMR (100MHz, CDCl ₃ ) δ162.4, 152.6, 146.5, 141.0, 140.3, 137.3, 136.6, 135.9, 133.9, 132.2 (q, J=32.0Hz), 130.3, 128.7, 126.4, 124.5, 124.2 (q, J=271.0Hz), 123.7 (q, J=4.0Hz), 122.8, 121.0, 116.6 (q, J=4.0Hz), 36.4, 35.0, 31.3, 31.0. The peaks of the molecular carbon spectrum can correspond to the target product one by one, and the number is reasonable. It can be seen from Fig. 8 that: ¹⁹ F NMR (100 MHz, CDCl ₃ ) δ-62.3. Combined with the results of the above NMR spectrum, carbon spectrum, and fluorine spectrum, it can be seen that the product obtained in Example 3 is 8-(tert-butyl)-10,10-dimethyl-11-phenyl-2-(trifluoro Methyl)-10H-indeno[1,2-b]quinoline (1c).

The preparation method in this example uses the Schiff base N-(4-(tert-butyl)phenyl)-1-(4-(trifluoromethyl) formed by the dehydration condensation of popular chemicals aromatic aldehyde and aromatic amine Phenyl)toluidine 2c and phenylpropargyl alcohol 3a undergo cycloaddition and intramolecular Friedel-Crafts reaction under the catalysis of transition metal trivalent rhodium catalyst [Cp*RhCl ₂ ] ₂ to obtain indenoquinoline derivatives in one step , with good atom economy and step economy, while solving the problem of regioselectivity generated by migratory insertion of alkynes in transition metal-catalyzed processes. This reaction activates three hydrogens on the Schiff base more, and in the next step of the phenyl propargyl alcohol coupling compound molecule, complex condensed heterocyclic indenoquinoline derivatives can be constructed with a higher yield (63%) Obtain the final target product compound 8-(tert-butyl)-10,10-dimethyl-11-phenyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline ( 1c).

Therefore, the preparation method of indenoquinoline derivatives in this example is a green and efficient synthesis method. The method has the characteristics of easy availability of raw materials, high atom economy and step economy. Efficient synthesis of indenoquinoline derivative compound 8-(tert-butyl)-10,10-dimethyl-11-phenyl-2-(trifluoromethyl)-10H-indene under milder reaction conditions And[1,2-b]quinoline (1c).

The chemical transformation of this application is compatible with the large steric hindrance tert-butyl group, and the applicable scope of the substrate is wide.

Example 4 Preparation of methyl 10,10-dimethyl-11-phenyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline-8-carboxylate (1d)

Under an atmosphere of atmospheric pressure air, add 4-((4-(trifluoromethyl)benzylidene)amino)methyl benzoate 2d (30.7mg, 0.10mmol), phenyl propargyl Alcohol 3a (16.0mg, 0.10mmol), trivalent rhodium catalyst [Cp*RhCl ₂ ] ₂ (2.5mg, 0.004mmol), silver trifluoromethanesulfonimide (3.9mg, 0.01mmol), silver acetate (33.4mg , 0.20mmol), dichloroethane (DCE, 1.0mL), react at a temperature of 100°C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, and then concentrated to obtain a crude product. The crude product was separated by thin chromatography on a prepared silica gel plate, and the selected developing solvent or eluent was a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 10:1, and with 56% Yield of the product 10,10-dimethyl-11-phenyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline-8-carboxylic acid methyl ester (1d) . The chemical reaction equation corresponding to this embodiment is as follows:

The H NMR spectrum, C NMR spectrum and F NMR spectrum of the compound prepared in Example 4 are shown in Figure 9, Figure 10 and Figure 11. It can be seen from Figure 9: ¹ H NMR (400MHz, CDCl ₃ ) δ8.13 (d, J=2.0Hz, 1H), 8.02-7.99 (m, 2H), 7.76 (d, J=8.0Hz, 1H) , 7.56-7.50 (m, 4H), 7.36 (dd, J = 1.6Hz, 7.6Hz, 2H), 6.92 (s, 1H), 3.93 (s, 3H), 1.46 (s, 6H). Molecular hydrogen spectrum peaks can correspond to the target product one by one, and the number is reasonable. It can be seen from Fig. 10 that: ¹³ C NMR (100MHz, CDCl ₃ ) δ166.6, 165.6, 147.5, 147.1, 145.9, 137.9, 136.3, 134.2, 133.8, 132.7 (q, J=32.0Hz), 130.9, 130.6, 130.2, 128.8, 128.7, 128.6, 127.5, 124.0 (q, J=271.0Hz), 124.1 (q, J=4.0Hz), 121.5, 116.9 (q, J=4.0Hz), 52.3, 36.4, 31.0. The peaks of the molecular carbon spectrum can correspond to the target product one by one, and the number is reasonable. It can be seen from Fig. 11 that: ¹⁹ F NMR (100 MHz, CDCl ₃ ) δ-62.5. Combined with the results of the above H NMR spectrum, carbon spectrum, and fluorine spectrum, it can be seen that the product obtained in Example 4 is 10,10-dimethyl-11-phenyl-2-(trifluoromethyl)-10H-indeno [1,2-b]Methyl quinoline-8-carboxylate (1d).

The preparation method of indenoquinoline derivatives in this example is to activate the carbon-hydrogen bond in the inert solvent dichloroethane solvent, that is, through a cascade reaction of multiple cycloadditions by a one-pot method, and the raw materials are easy to obtain , no need for pre-functionalization, good atom and step economy, and the catalytic reaction has the advantages of good functional group compatibility and a wide range of substrates. The reaction in this embodiment only needs to stir the reaction for 12 hours at a milder temperature of 100° C. in an atmosphere of 1 atmospheric pressure, then cool it down, and then carry out a series of follow-up treatments, which can be achieved with a good yield (56%) Obtain the final target product compound 10,10-dimethyl-11-phenyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline-8-carboxylic acid methyl ester (1d ).

Therefore, the preparation method of indenoquinoline derivatives in this example has high efficiency and good regioselectivity. At the same time, the method only uses simple and easy-to-obtain Schiff bases as reaction substrates, and has good atom economy. The product is water.

The chemical transformation in this example contains an easy-to-transform group such as an ester group, and subsequent transformations can be performed later.

Example 5 Preparation of 10,10-dimethyl-8-phenoxy-11-phenyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline (1e)

Under an atmosphere of atmospheric pressure air, N-(4-phenoxyphenyl)-1-(4-(trifluoromethyl)phenyl)toluidine 2e (34.1mg, 0.10mmol ), phenylpropargyl alcohol 3a (16.0mg, 0.10mmol), trivalent rhodium catalyst [Cp*RhCl ₂ ] ₂ (2.5mg, 0.004mmol), silver hexafluoroantimonate (3.4mg, 0.01mmol), silver acetate (33.4mg, 0.20mmol), dichloroethane (DCE, 1.0mL), react at a temperature of 100°C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, and then concentrated to obtain a crude product. The crude product was separated by thin chromatography on a prepared silica gel plate, the selected developing solvent or eluent was a mixed solvent of sherwood oil and ethyl acetate, and the volume ratio of sherwood oil and ethyl acetate was 20:1, with 67% The yield of the product 10,10-dimethyl-8-phenoxy-11-phenyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline (1e) . The chemical reaction equation corresponding to this embodiment is as follows:

The H NMR, C NMR, and F NMR spectra of the compound prepared in Example 5 are shown in Figure 12, Figure 13 and Figure 14. It can be seen from Figure 12: ¹ H NMR (400MHz, CDCl ₃ ) δ7.99 (d, J=7.6Hz, 1H), 7.67 (d, J=8.8Hz, 1H), 7.55-7.48 (m, 4H) ,7.39-7.35(m,4H),7.16(d,J=7.6Hz,1H),7.13(d,J=2.8Hz,1H),7.06(d,J=8.0Hz,2H),6.94(s, 1H), 6.90 (dd, J=2.4Hz, 8.4Hz, 1H), 1.41 (s, 6H). Molecular hydrogen spectrum peaks can correspond to the target product one by one, and the number is reasonable. It can be seen from Figure 13 that: ¹³ C NMR (100MHz, CDCl ₃ ) δ162.1, 158.3, 156.4, 146.7, 145.9, 140.2, 138.3, 134.2, 134.1, 132.2 (q, J=32.0Hz), 132.1, 130.9, 129.9, 128.9, 128.8, 128.6, 128.3, 124.1 (q, J = 271.0Hz), 123.9, 123.7 (q, J = 4.0Hz), 121.0, 119.3, 116.7 (q, J = 4.0Hz), 116.6, 116.3, 36.7, 31.1. The peaks of the molecular carbon spectrum can correspond to the target product one by one, and the number is reasonable. It can be seen from Fig. 14 that: ¹⁹ F NMR (100 MHz, CDCl ₃ ) δ-62.2. Combined with the results of the above proton NMR spectrum, carbon spectrum, and fluorine spectrum, it can be seen that the product obtained in Example 5 is 10,10-dimethyl-8-phenoxy-11-phenyl-2-(trifluoromethyl )-10H-indeno[1,2-b]quinoline (1e).

In this example, based on the strategy of orderly and multiple activation of carbon-hydrogen bonds, indenoquinolines were obtained by orderly [3+2] and [4+2] cyclization reactions of Schiff bases and propargyl alcohols catalyzed by metal catalysts Derivatives. Among them, the alcoholic hydroxyl group serves as the core transient directing group and activating group, assisting the regioselectivity of alkyne insertion and the subsequent cascade of Friedel-Crafts-type reactions of in situ carbocation intermediates.

This reaction synthesizes the indenoquinoline derivative 10,10-dimethyl-8-phenoxy-11-phenyl-2-(trifluoromethyl)-10H-indeno[ 1,2-b]quinoline (1e), the C-H activation of the bisaryl group and the C-H bond activation of the imine C-H bond activation process in the reaction mode, one-step synthesis of complex fused heterocycles. This indenoquinoline skeleton widely exists in natural products and exhibits good antitumor activity.

Example 6 8-methoxy-11-(4-methoxyphenyl)-10,10-dimethyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinone Preparation of morphine (1f)

Under an atmosphere of atmospheric pressure air, N-(4-methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)toluidine 2a (27.9mg, 0.10mmol ), 4-methoxyphenyl propargyl alcohol 3b (19.0mg, 0.10mmol), trivalent rhodium catalyst [Cp*RhCl ₂ ] ₂ (2.5mg, 0.004mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01mmol), silver acetate (33.4mg, 0.20mmol), dichloroethane (DCE, 1.0mL), react at a temperature of 100°C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, and then concentrated to obtain a crude product. The crude product was separated by thin chromatography on a prepared silica gel plate. The selected developing solvent or eluent was a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether and ethyl acetate mixed solvent was 10:1. % yield of the product 8-methoxy-11-(4-methoxyphenyl)-10,10-dimethyl-2-(trifluoromethyl)-10H-indeno[1,2 -b] quinoline (1f). The chemical reaction equation corresponding to this embodiment is as follows:

The H NMR, C NMR, and F NMR spectra of the compound prepared in Example 6 are shown in Figure 15, Figure 16 and Figure 17. It can be seen from Figure 15 that: ¹ H NMR (400MHz, CDCl ₃ ) δ7.97(d, J=7.6Hz, 1H), 7.66(d, J=8.8Hz, 1H), 7.52(d, J=6.4Hz ,1H),7.28(dd,J=2.0Hz,7.2Hz,2H),7.05(dd,J=1.6Hz,6.4Hz,2H),6.98(d,J=2.8Hz,1H),6.96(s, 1H), 6.87 (dd, J = 2.8Hz, 8.4Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 1.44 (s, 6H). Molecular hydrogen spectrum peaks can correspond to the target product one by one, and the number is reasonable. It can be seen from Fig. 16 that: ¹³ C NMR (100MHz, CDCl ₃ ) δ161.2, 160.4, 159.5, 146.8, 145.4, 140.1, 136.9, 136.6, 134.4, 132.0, 131.9 (q, J=31.0Hz), 130.9, 130.2, 128.8, 127.5, 127.2(q, J=270.0Hz), 126.3, 125.5(q, J=3.0Hz), 123.5(q, J=4.0Hz), 120.7, 116.5(q, J=4.0Hz), 115.0, 114.2, 114.0, 112.8, 111.4, 55.5, 55.3, 36.6, 31.2. It can be seen from Fig. 17 that: ¹⁹ F NMR (100 MHz, CDCl ₃ ) δ-62.2. Combined with the results of the above H NMR spectrum, carbon spectrum, and fluorine spectrum, it can be seen that the product obtained in Example 6 is 8-methoxy-11-(4-methoxyphenyl)-10,10-dimethyl- 2-(Trifluoromethyl)-10H-indeno[1,2-b]quinoline (1f).

In this example, the indenoquinoline derivative 8-methoxy-11-(4-methoxyphenyl)-10,10-dimethyl-2-(trifluoromethyl)-10H-indene The preparation method of the [1,2-b]quinoline (1f) has few steps, is easy to operate, and has a very wide application range for substrates, and is also easy for subsequent further transformations. The invention of this application has good atom economy, and the by-product is water, and has efficient step economy and atom economy.

The chemical conversion in this example is compatible with trifluoromethyl, which is widely used in the fields of materials and medicine.

Example 7 4-(8-methoxy-10,10-dimethyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinolin-11-yl)benzoic acid ethyl Preparation of ester (1 g)

Under an atmosphere of atmospheric pressure air, N-(4-methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)toluidine 2a (27.9mg, 0.10mmol ), ethyl 4-(3-hydroxy-3-methylbut-1-yn-1-yl)benzoate 3c (23.2mg, 0.10mmol), trivalent rhodium catalyst [Cp*RhCl ₂ ] ₂ (2.5mg , 0.004mmol), silver trifluoromethanesulfonimide (3.9mg, 0.01mmol), silver acetate (33.4mg, 0.20mmol), dichloromethane (DCM, 1.0mL), react at a temperature of 80°C for 18 hours . After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, and then concentrated to obtain a crude product. The crude product was separated by thin chromatography on a prepared silica gel plate, the selected developing solvent or eluent was a mixed solvent of sherwood oil and ethyl acetate, and the volume ratio of sherwood oil and ethyl acetate was 10:1, with 60% The yield of the obtained product 4-(8-methoxy-10,10-dimethyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinolin-11-yl)benzene Ethyl formate (1 g). The chemical reaction equation corresponding to this embodiment is as follows:

The H NMR spectrum, C NMR spectrum and F NMR spectrum of the compound prepared in Example 7 are shown in Figure 18, Figure 19 and Figure 20. It can be seen from Figure 18: ¹ H NMR (400MHz, CDCl ₃ ) δ8.21 (d, J=8.4Hz, 2H), 7.99 (d, J=7.6Hz, 1H), 7.68 (d, J=8.4Hz ,1H),7.54(d,J=7.2Hz,1H),7.46(d,J=8.0Hz,2H),6.97(d,J=2.8Hz,1H),6.90-6.87(m,2H),4.45 (q, J=7.2Hz, 2H), 3.86(s, 3H), 1.45(t, J=7.2Hz, 3H), 1.42(s, 6H). Molecular hydrogen spectrum peaks can correspond to the target product one by one, and the number is reasonable. It can be seen from Fig. 19 that: ¹³ C NMR (100MHz, CDCl ₃ ) δ166.2, 160.7, 160.6, 146.0, 144.0, 139.8, 139.4, 136.8, 136.5, 134.8, 132.3, 131.4 (q, J=32.0Hz), 130.9, 130.6, 129.8, 129.2, 128.8, 124.1 (q, J = 271.0Hz), 123.8 (q, J = 4.0Hz), 121.0, 116.4 (q, J = 3.0Hz), 112.8, 111.5, 61.2, 55.5, 36.7, 31.3, 14.4. It can be seen from Fig. 20 that: ¹⁹ FNMR (100 MHz, CDCl ₃ ) δ-62.3. Combined with the results of the above H NMR spectrum, carbon spectrum, and fluorine spectrum, it can be seen that the product obtained in Example 7 is 4-(8-methoxyl-10,10-dimethyl-2-(trifluoromethyl)- 10H-Indeno[1,2-b]quinolin-11-yl)ethyl benzoate (1 g).

In the present embodiment, using multiple dehydrogenation strategies, under the promotion of a trivalent rhodium metal catalyst, N-(4-methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)toluidine 2a Alkyne cycloaddition and intramolecular Friedel-Crafts reaction with ethyl 4-(3-hydroxy-3-methylbut-1-yn-1-yl)benzoate 3c achieved high efficiency (60 %) Indenoquinoline derivatives were prepared with high selectivity. The reaction in this embodiment only needs to be reacted for 12 hours at 100° C. under atmospheric air atmosphere, then cooled, and then a series of follow-up treatments can be performed to obtain the final target product compound with a higher yield (60%): Ethyl 4-(8-methoxy-10,10-dimethyl-2-(trifluoromethyl)-10H-indeno[1,2-b]quinolin-11-yl)benzoate (1g ).

Therefore, the preparation method of indenoquinoline derivatives in this example is a green and efficient synthesis method. This method does not require complex pre-synthesis of some substrates, and does not require cumbersome synthesis steps. It does not need to use a large amount of reagents that seriously endanger the environment such as strong acids or bases in the reaction. Therefore, it is environmentally friendly and safe. After one-step synthesis, it can be obtained efficiently. product. Efficient synthesis of indenoquinoline derivative compound 4-(8-methoxy-10,10-dimethyl-2-(trifluoromethyl)-10H-indeno[1, 2-b] Ethyl quinolin-11-yl)benzoate (1 g). All the raw materials in the reaction are cheap and easy to obtain, the method is simple and easy to operate, and the operation is safe, so it has potential practical value.

The chemical transformation of this application is compatible with trifluoromethyl, which is widely used in the fields of materials and medicine.

Example 8 Preparation of 8,10,10-trimethyl-11-(thiophen-3-yl)-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline (1h)

Under an atmosphere of atmospheric pressure air, N-p-tolyl-1-(4-(trifluoromethyl)phenyl)toluidine 2f (23.6mg, 0.10mmol), 2-methyl -4-(thiophen-3-yl)but-3-yn-2-ol 3d (16.6mg, 0.10mmol), divalent ruthenium catalyst [Ru(p-cymene)Cl ₂ ] ₂ (2.5mg, 0.004mmol) , silver trifluoromethanesulfonyl imide (3.9mg, 0.01mmol), silver acetate (33.4mg, 0.20mmol), dichloroethane (DCE, 1.0mL), react at a temperature of 100°C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, and then concentrated to obtain a crude product. The crude product was separated by thin chromatography on a prepared silica gel plate, and the selected developing solvent or eluent was a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 30:1, and with 53% Yield of the obtained product 8,10,10-trimethyl-11-(thien-3-yl)-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline (1h) . The chemical reaction equation corresponding to this embodiment is as follows:

The H NMR, C NMR, and F NMR spectra of the compound prepared in Example 8 are shown in Figure 21, Figure 22 and Figure 23. It can be seen from Figure 21: ¹ H NMR (400MHz, CDCl ₃ ) δ7.99 (d, J=7.6Hz, 1H), 7.61 (d, J=7.6Hz, 1H), 7.55-7.53 (m, 2H) ,7.35(dd,J=1.2Hz,3.2Hz,1H),7.26(s,1H),7.17-7.14(m,2H),7.05(s,1H),2.41(s,3H),1.47(s, 6H). Molecular hydrogen spectrum peaks can correspond to the target product one by one, and the number is reasonable. It can be seen from Fig. 22 that: ¹³ C NMR (100MHz, CDCl ₃ ) δ162.2, 146.5, 141.0, 140.4, 139.6, 137.8, 136.6, 135.7, 133.9, 132.2 (q, J=32.0Hz), 130.7, 128.7, 128.2, 126.7, 126.4, 124.5, 124.2 (q, J=271.0Hz), 123.7 (q, J=4.0Hz), 121.0, 116.6 (q, J=4.0Hz), 36.2, 30.9, 21.6. It can be seen from Fig. 23 that: ¹⁹ F NMR (100 MHz, CDCl ₃ ) δ-62.3. Combined with the results of the above H NMR spectrum, carbon spectrum, and fluorine spectrum, it can be known that the product obtained in Example 8 is 8,10,10-trimethyl-11-(thiophen-3-yl)-2-(trifluoroform yl)-10H-indeno[1,2-b]quinoline (1h).

The preparation method in this embodiment uses the Schiff base N-p-tolyl-1-(4-(trifluoromethyl)phenyl)toluidine 2f and 2 -Methyl-4-(thiophen-3 _- yl)but-3-yn-2-ol _3d undergoes cycloaddition and molecular The inner Friedel-Crafts reaction yields indenoquinoline derivatives in one step, which has good atom economy and step economy, and simultaneously solves the problem of regioselectivity generated by migratory insertion of alkynes in transition metal-catalyzed processes. This reaction activates the three hydrogens on the Schiff base more, and in the next step of the phenyl propargyl alcohol coupling molecule, the complex condensed heterocyclic indenoquinoline derivative can be constructed with a good yield (53%) Obtain the final target product compound 8,10,10-trimethyl-11-(thiophen-3-yl)-2-(trifluoromethyl)-10H-indeno[1,2-b]quinoline (1h ).

Therefore, the preparation method of indenoquinoline derivatives in this example is a green and efficient synthesis method. The method has the characteristics of easy availability of raw materials, high atom economy and step economy. Efficient synthesis of indenoquinoline derivatives 8,10,10-trimethyl-11-(thiophen-3-yl)-2-(trifluoromethyl)-10H-indeno under milder reaction conditions [1,2-b]quinoline (1h).

The chemical transformation of the application contains a thiophene heterocycle, which provides a new synthesis idea in the field of organic materials.

Example 9 Preparation of 2-methoxy-13,13-dimethyl-12-phenyl-13H-benzo[5,6]indeno[1,2-b]quinoline (1i)

Under an atmosphere of atmospheric pressure air, 2 g (26.1 mg, 0.10 mmol) of N-(4-methoxyphenyl)-1-(naphthalene-2-yl) toluidine, phenylalkyne Propanol 3a (16.0mg, 0.10mmol), trivalent rhodium catalyst [Cp*RhCl ₂ ] ₂ (2.5mg, 0.004mmol), silver trifluoromethanesulfonimide (3.9mg, 0.01mmol), silver acetate (33.4 mg, 0.20mmol), dichloroethane (DCE, 1.0mL), react at a temperature of 100°C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, and then concentrated to obtain a crude product. The crude product is separated by thin chromatography on a prepared silica gel plate, the selected developing solvent or eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 20:1, with 59% Yield The product 2-methoxy-13,13-dimethyl-12-phenyl-13H-benzo[5,6]indeno[1,2-b]quinoline (1i) was obtained. The chemical reaction equation corresponding to this embodiment is as follows:

The H NMR and C NMR spectra of the compound prepared in Example 9 are shown in Figure 24 and Figure 25. It can be seen from Figure 24: ¹ H NMR (400MHz, CDCl ₃ ) δ8.35(s, 1H), 7.91(t, J=4.8Hz, 1H), 7.71(q, J=3.6Hz, 1H), 7.66 -7.63(m,2H),7.54-7.49(m,3H),7.43-7.41(m,3H),7.01(s,1H),6.97(d,J＝2.8Hz,1H),6.86(dd,J =2.8Hz, 8.8Hz, 1H), 3.85(s, 3H), 1.45(s, 6H). Molecular hydrogen spectrum peaks can correspond to the target product one by one, and the number is reasonable. It can be seen from Figure 25 that: ¹³ C NMR (100MHz, CDCl ₃ ) δ167.7, 161.9, 159.6, 143.3, 139.3, 137.2, 135.2, 135.0, 132.8, 132.4, 130.9, 130.9, 129.6, 129.2, 128.8, 128.6, 128. 128.0, 127.0, 126.0, 121.1, 118.9, 112.7, 111.3, 55.5, 36.7, 31.4. Combined with the results of the above H NMR spectrum and carbon spectrum, it can be seen that the product obtained in Example 9 is 2-methoxy-13,13-dimethyl-12-phenyl-13H-benzo[5,6]indene And[1,2-b]quinolines (1i).

The preparation method of indenoquinoline derivatives in this example is to activate the carbon-hydrogen bond in the inert solvent dichloroethane solvent, that is, through a cascade reaction of multiple cycloadditions by a one-pot method, and the raw materials are easy to obtain , no need for pre-functionalization, good atom and step economy, and the catalytic reaction has the advantages of good functional group compatibility and a wide range of substrates. The reaction in this embodiment only needs to stir the reaction for 12 hours at a milder temperature of 100° C. in an atmosphere of 1 atmospheric pressure, then cool it down, and then carry out a series of follow-up treatments, which can be achieved with a good yield (59%) The final target product compound 2-methoxy-13,13-dimethyl-12-phenyl-13H-benzo[5,6]indeno[1,2-b]quinoline (1i) was obtained.

Therefore, the preparation method of indenoquinoline derivatives in this example has high efficiency and good regioselectivity. At the same time, the method only uses simple and easy-to-obtain Schiff bases as reaction substrates, and has good atom economy. The product is water.

The chemical transformation of the application is compatible with the naphthalene ring, and the obtained product can be applied in the field of organic light-emitting, and can provide a new synthesis method for it.

Example 10 Preparation of 2,8-dimethoxy-10,10-dimethyl-11-(thiophen-3-yl)-10H-indeno[1,2-b]quinoline (1j)

Under an atmosphere of atmospheric pressure air, N,1-bis(4-methoxyphenyl)toluidine 2h (24.1mg, 0.10mmol), 2-methyl-4-(thiophene-3 -yl)but-3-yn-2-ol 3d (16.6mg, 0.10mmol), trivalent rhodium catalyst [Cp*RhCl ₂ ] ₂ (2.5mg, 0.004mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01mmol), silver acetate (33.4mg, 0.20mmol), dichloroethane (DCE, 1.0mL), react at a temperature of 100°C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, and then concentrated to obtain a crude product. The crude product was separated by thin chromatography on a prepared silica gel plate, the selected developing solvent or eluent was a mixed solvent of sherwood oil and ethyl acetate, and the volume ratio of sherwood oil and ethyl acetate was 30:1, with 62% Yield The product 2,8-dimethoxy-10,10-dimethyl-11-(thien-3-yl)-10H-indeno[1,2-b]quinoline (1j) was obtained. The chemical reaction equation corresponding to this embodiment is as follows:

The H NMR and C NMR spectra of the compound prepared in Example 10 are shown in Figure 26 and Figure 27. It can be seen from Figure 26: ¹ H NMR (400MHz, CDCl ₃ ) δ7.80 (d, J=8.0Hz, 1H), 7.61 (d, J=8.4Hz, 1H), 7.47 (dd, J=2.8Hz ,4.8Hz,1H),7.30(d,J=2.0Hz,1H),7.12(d,J=4.8Hz,1H),6.96(d,J=3.6Hz,1H),6.84(dd,J=2.8 Hz,8.8Hz,1H),6.72(dd,J=2.4Hz,8.0Hz,1H),6.39(d,J=2.4Hz,1H),3.85(s,3H),3.79(s,3H),1.48 (s,6H). Molecular hydrogen spectrum peaks can correspond to the target product one by one, and the number is reasonable. It can be seen from Figure 27 that: ¹³ C NMR (100MHz, CDCl ₃ ) δ162.3, 161.6, 159.6, 148.0, 140.7, 139.5, 137.0, 135.2, 134.7, 131.1, 129.9, 129.0, 128.6, 125.8, 125.7, 125.1, 124. 122.2, 120.3, 114.5, 112.7, 111.2, 109.9, 107.8, 55.6, 55.4, 36.3, 31.0. Combined with the results of the above H NMR spectrum and carbon spectrum, it can be seen that the product obtained in Example 10 is 2,8-dimethoxy-10,10-dimethyl-11-(thiophen-3-yl)-10H- Indeno[1,2-b]quinoline (1j).

In this example, based on the strategy of orderly and multiple activation of carbon-hydrogen bonds, indenoquinolines were obtained by orderly [3+2] and [4+2] cyclization reactions of Schiff bases and propargyl alcohols catalyzed by metal catalysts Derivatives. Among them, the alcoholic hydroxyl group serves as the core transient directing group and activating group, assisting the regioselectivity of alkyne insertion and the subsequent cascade of Friedel-Crafts-type reactions of in situ carbocation intermediates.

This reaction synthesizes the indenoquinoline derivative 2,8-dimethoxy-10,10-dimethyl-11-(thiophen-3-yl)-10H-indeno[1 ,2-b] quinoline (1j), the C-H activation of the bisaryl group and the C-H bond activation of the imine C-H bond activation process occurred in the reaction mode, and the complex fused heterocycle was synthesized in one step. This indenoquinoline skeleton widely exists in natural products and exhibits good antitumor activity.

In summary, the preparation method of indenoquinoline derivatives provided by this patent application is based on the strategy of orderly and multiple carbon-hydrogen bond activation, and the ordered [3+ 2] and [4+2] cyclization reactions to obtain indenoquinoline derivatives. Among them, the alcoholic hydroxyl group serves as the core transient directing group and activating group, assisting the regioselectivity of alkyne insertion and the subsequent cascade of Friedel-Crafts-type reactions of in situ carbocation intermediates. Therefore, the transformation is highly efficient and regioselective, and the method only uses simple and readily available Schiff bases as reaction substrates, with good atom economy, and the by-product is water.

More importantly, the reaction synthesizes indenoquinoline derivatives from two simple raw materials in one step. In the reaction mode, the C-H activation of the bisaryl group and the three carbon-hydrogen bond activation processes of the C-H bond activation of the imine occur. The one-step synthesis is complex. Fused heterocycle.

At the same time, the preparation method of the indenoquinoline derivatives in this patent application has a very wide range of substrates (for example, it is compatible with trifluoromethyl, which is widely used in materials and medical fields, contains easily transformable functional group bromine, and can Compatible with tert-butyl groups with large steric hindrance, easy-to-transform group ester groups, thiophene heterocycles and naphthalene rings), and are also easy to follow-up further transformations.

In the description of this specification, descriptions referring to the terms "one embodiment", "some embodiments", "exemplary embodiments", "examples", "specific examples", or "some examples" etc. mean that the embodiments are combined Specific features, structures, materials, or characteristics described in or examples are included in at least one embodiment or example of the present patent application. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the described specific features, structures, materials or characteristics may be combined in any suitable manner in any one or more embodiments or examples.

Although several embodiments of the patent application have been shown and described, those skilled in the art can understand that various changes, modifications, Alternatives and modifications, the scope of this patent application is defined by the claims and their equivalents.

Claims (10)

1. A method for preparing indenoquinoline derivatives is characterized in that: in an inert solvent, under the action of a metal catalyst, a Schiff base compound (formula II) and a propargyl alcohol compound (formula III) are reacted to obtain an indenoquinoline derivative (formula I), wherein the reaction equation is as follows:

wherein Ar is benzene and naphthalene containing trifluoromethyl, halogen, ether and other substituent groups, R ¹ Is alkyl, ester, ether, etc., R ² Is phenyl and thiophene substituted by ether and ester groups.

2. The method for producing an indenoquinoline derivative according to claim 1, characterized in that: the inert solvent is one or more of toluene, tetrahydrofuran, 1, 4-dioxane, N' -dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, 1, 2-dichloroethane, ethanol and trifluoroethanol.

3. The method for producing an indenoquinoline derivative according to claim 1, characterized in that: the metal catalyst is as follows: any one or more of pentamethylcyclopentadienylrhodium chloride dimer, dichlorobis (4-methylisopropylphenyl) ruthenium, pentamethylcyclopentadienyliridium chloride dimer and trisacetonitrile-pentamethylcyclopentadienylrhodium chloride dimer.

4. The method for producing an indenoquinoline derivative according to claim 1, characterized in that: the halogen atom seizing agent is one or the combination of silver hexafluoroantimonate and bis-trifluoromethyl sulfonyl imide silver.

5. The method for producing an indenoquinoline derivative according to claim 1, characterized in that: the oxidant is one or more of silver acetate, silver carbonate, copper acetate and silver oxide.

6. The method for producing an indenoquinoline derivative according to claim 1, characterized in that: the dosage of the metal catalyst is 2mol% of the dosage of the Schiff base compound (formula II).

7. The method for producing an indenoquinoline derivative according to claim 1, characterized in that: the dosage of the halogen atom seizing agent is 5mol percent of the dosage of the Schiff base compound (formula II).

8. The method for producing an indenoquinoline derivative according to claim 1, characterized in that: the reaction temperature is 80-120 ℃.

9. The method for producing an indenoquinoline derivative according to claim 7, wherein the reaction is carried out for 12 to 24 hours.

10. The method for producing an indenoquinoline derivative according to claim 1, characterized in that: the method comprises the following specific operation steps:

s1: in a reactor, 2.5mg of pentamethylcyclopentadienyl rhodium chloride dimer, 3.9mg of silver trifluoromethanesulfonylimide, 39.8mg of silver acetate, 1.0mL of dichloroethane as a solvent, 55.8mg of Schiff base and 47.2mg of phenyl propargyl alcohol are sequentially added into the air;

s2: the reaction is carried out for 12 hours at the temperature of 100 ℃;

s3: and after the reaction is finished, separating the mixture by using a column chromatography separation technology to obtain the target compound.

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