CN114014805B - Preparation method of trifluoromethylated 2,4-quinolinedione compounds - Google Patents

Abstract

The application discloses a preparation method of a trifluoromethyl 2, 4-quinoline diketone compound, which comprises the following steps: adding N-o-cyano aryl acrylamide compound, sodium trifluoromethyl sulfinate, photocatalyst and solvent into a reactor, stirring for reaction under the conditions of air atmosphere and visible light irradiation, concentrating after the reaction is completed, and separating by silica gel column chromatography to obtain the trifluoromethyl 2, 4-quinolinedione compound. The method can generate reaction at room temperature without using transition metal catalysis, and the used oxidant is oxygen in air, so that the addition of other oxidants with strong oxidability can be avoided.

Description

Preparation method of trifluoromethylated 2,4-quinolinedione compounds

technical field

The invention relates to the technical field of compound synthesis. More specifically, the present invention relates to a method for preparing trifluoromethylated 2,4-quinolinedione compounds.

Background technique

As an important class of nitrogen-containing heterocyclic compounds, 2,4-quinolinediones have rich pharmacological activities, such as anticancer, antiviral, and antimalarial. They are also important intermediates for the construction of other nitrogen-containing heterocyclic skeletons. In view of the importance of 2,4-quinolinedione compounds, the development of preparation methods for such compounds has always been an important research topic in the field of organic synthetic chemistry. Due to the extremely strong electronegativity of fluorine atoms, the introduction of trifluoromethyl groups into organic compounds can significantly improve the physical and chemical properties of compounds such as lipophilicity and solubility. Based on this, trifluoromethyl-containing compounds are widely used in the fields of pesticides, medicines and materials. While constructing 2,4-quinolinedione compounds, introducing trifluoromethyl into the molecule can efficiently synthesize trifluoromethylated 2,4-quinolinedione compounds with potential application value.

Through literature research, it is found that the preparation methods of trifluoromethylated 2,4-quinolinedione compounds are less studied. In 2016, Professor Li Yamin of Kunming University of Science and Technology developed a method for the efficient preparation of trifluoromethylated 2,4-quinoline diones based on a copper-catalyzed radical tandem cyclization strategy (Advanced Synthesis & Catalysis, 2016, 358 , 3616-3626), providing a material basis for the application research of this kind of compound. However, this reaction requires the use of equivalent copper perchlorate as an oxidant, which limits the scale-up application of this reaction to some extent. Therefore, it is particularly important to develop a synthetic method with milder conditions to prepare trifluoromethylated 2,4-quinolinediones.

Contents of the invention

The purpose of the present invention is to provide a preparation method of trifluoromethylated 2,4-quinolinedione compounds. The oxidant used in the method is oxygen in the air, which can avoid additional addition of other strong oxidizing oxidants, and can reduce side effects. reaction occurs.

In order to achieve these objects and other advantages according to the present invention, a preparation method of trifluoromethylated 2,4-quinolinedione compounds is provided, comprising:

Add N-o-cyanoaryl acrylamide compound, sodium trifluoromethyl sulfinate, photocatalyst and solvent successively into the reactor, then stir the reaction under air atmosphere and visible light irradiation condition, after the reaction is complete, Concentrate and separate by silica gel column chromatography to obtain trifluoromethylated 2,4-quinolinedione compounds.

Preferably, in the preparation method of the trifluoromethylated 2,4-quinolinediones, the photocatalyst is rose bengal.

Preferably, in the preparation method of trifluoromethylated 2,4-quinolinedione compounds, the solvent is acetonitrile.

Preferably, in the preparation method of trifluoromethylated 2,4-quinolinedione compounds, after adding the raw materials, the reaction is stirred at room temperature, in an air atmosphere, and under blue light irradiation conditions.

Preferably, in the preparation method of trifluoromethylated 2,4-quinolinedione compounds, the stirring reaction time is 24 hours.

Preferably, in the preparation method of the described trifluoromethylated 2,4-quinolinedione compound, the feeding mole of N-o-cyanoarylalacrylamide compound and sodium trifluoromethyl sulfinate The ratio is 1:3.

Preferably, in the preparation method of trifluoromethylated 2,4-quinolinedione compounds, the molar ratio of N-o-cyanoaryl acrylamide compounds and photocatalyst is 1:0.05.

Preferably, in the preparation method of the described trifluoromethylated 2,4-quinolinedione compounds, the N-o-cyanoaryl acrylamide compound is N-methyl-N-(2-cyano phenyl)-2-methacrylamide, N-methyl-N-(2-cyano-4-chlorophenyl)-2-methacrylamide, N-methyl-N-(2-cyano yl-3-chlorophenyl)-2-methacrylamide or N-methyl-N-(2-cyano-3-bromophenyl)-2-methacrylamide.

The present invention at least includes the following beneficial effects:

The present invention uses sodium trifluoromethyl sulfinate and N-o-cyanoaryl acrylamide compounds as reaction raw materials, and realizes the synthesis of olefins while constructing two C–C bonds under visible light-promoted oxidation-reduction catalysis conditions. A series of trifluoromethylated 2,4-quinolinediones were prepared through the acylation reaction of trifluoromethylation. Compared with the existing methods for preparing trifluoromethylated 2,4-quinolinedione compounds, the synthesis method used in the present invention does not require transition metal catalysis, and the reaction can occur at room temperature, and the reaction conditions are milder and more Green and environment-friendly; the oxidant used is oxygen in the air, which can avoid adding other strong oxidizing oxidants and reduce the occurrence of side reactions; the photosensitizer used is Rose Bengal, which is one of the most common organic dyes, which is cheap and easy to obtain. The technical solution of the invention is more economical.

Other advantages, objectives and features of the present invention will partly be embodied through the following descriptions, and partly will be understood by those skilled in the art through the research and practice of the present invention.

Detailed ways

The present invention will be further described in detail below in conjunction with the embodiments, so that those skilled in the art can implement it with reference to the description.

It should be noted that the experimental methods described in the following embodiments, unless otherwise specified, are conventional methods, and the reagents and materials, unless otherwise specified, can be obtained from commercial sources;

According to the method reported in the existing literature (Organic & Biomolecular Chemistry, 2015, 13, 5376-5380), the reaction raw materials required for the technology of the present invention were synthesized. Concrete synthetic scheme is as follows:

The preparation method of trifluoromethylated 2,4-quinolinediones, comprising:

Add N-o-cyanoaryl acrylamide compound, sodium trifluoromethyl sulfinate, photocatalyst and solvent successively into the reactor, then stir the reaction under air atmosphere and visible light irradiation condition, after the reaction is complete, Concentrate and separate by silica gel column chromatography to obtain trifluoromethylated 2,4-quinolinedione compounds.

In another technical scheme, in the preparation method of the trifluoromethylated 2,4-quinolinedione compound, the photocatalyst is rose bengal.

In another technical scheme, in the preparation method of the trifluoromethylated 2,4-quinolinedione compound, the solvent is acetonitrile.

In another technical scheme, in the preparation method of the trifluoromethylated 2,4-quinolinedione compound, after adding raw materials, the reaction is stirred under room temperature, air atmosphere, and blue light irradiation conditions.

In another technical solution, in the preparation method of trifluoromethylated 2,4-quinolinedione compounds, the stirring reaction time is 24 hours.

In another technical scheme, in the preparation method of the described trifluoromethylated 2,4-quinolinedione compounds, N-o-cyanoaryl acrylamide compounds and trifluoromethylsulfinic acid The feeding molar ratio of sodium is 1:3.

In another technical scheme, in the preparation method of the described trifluoromethylated 2,4-quinolinedione compound, the molar ratio of N-o-cyanoarylalacrylamide compound and photocatalyst is 1 :0.05

In another technical scheme, in the preparation method of the described trifluoromethylated 2,4-quinoline diketones, the N-o-cyanoaryl acrylamides are N-methyl-N- (2-cyanophenyl)-2-methacrylamide, N-methyl-N-(2-cyano-4-chlorophenyl)-2-methacrylamide, N-methyl-N- (2-cyano-3-chlorophenyl)-2-methacrylamide or N-methyl-N-(2-cyano-3-bromophenyl)-2-methacrylamide.

The method for preparing trifluoromethylated 2,4-quinolinedione compounds in the present invention is mainly based on the radical tandem cyclization reaction promoted by visible light, using commercially purchased sodium trifluoromethyl sulfinate as trifluoromethyl Radical source, using the above-mentioned N-o-cyanoaryl acrylamide compound synthesized according to the literature method as a free radical acceptor substance, using a commercially purchased organic dye Rose Bengal (RB) as a photocatalyst, acetonitrile as a solvent, in the air Under the condition of atmosphere and room temperature, the target product can be synthesized by irradiation with blue light.

In the product structure, Ar represents the aromatic group connected with different substituents on the benzene ring; R represents the alkyl substituents such as methyl and benzyl; R' represents the alkyl substituents such as methyl and benzyl or aromatic groups such as phenyl. base substituents.

1. Screening of reaction conditions

After carrying out the synthesis work of the reaction raw materials, in order to investigate whether the design idea of synthesizing trifluoromethylated quinolinone derivatives under visible light is reasonable, we first use N-methyl-N-(2-cyanophenyl)-2- Methacrylamide (1a) and sodium trifluoromethanesulfinate (2) were used as template substrates, eosin Y disodium salt was used as photocatalyst, acetonitrile (MeCN) was used as solvent, and blue LED light was used as light source. Stirring reaction 24h under air atmosphere condition, the product that finds to obtain is just our target product trifluoromethylated quinolinone derivative (3a), and yield is 40%, and for improving yield, we have studied reaction condition to yield rate, and the reaction conditions were further optimized.

1.1 The influence of solvent on the reaction

Research 1,2-dichloroethane (DCE), tetrahydrofuran (THF), dichloromethane (DCM), dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N -The influence of solvents such as dimethylacetamide (DMA) and acetonitrile and water ratio of 4:1 on the reaction, the results are shown in Table 1.

The influence of table 1 solvent on reaction

Preparation method: sequentially add 0.2 mmol of 1a, 0.6 mmol of 2, eosin Y disodium salt (2 mol%) and 2 mL of solvent into a test tube, and stir under a blue LED light for 24 hours at room temperature and in an air atmosphere.

In the reaction process, the reaction can be completed except that dimethyl sulfoxide (DMSO), acetonitrile (CH ₃ CN) and acetonitrile and water 4:1 are used as solvents, and the raw materials still remain when the reaction is carried out under other solvent conditions. As can be seen from Table 1, the yield is the highest when the solvent is acetonitrile, which is 40%, and the yield drops to 22% after adding water to acetonitrile, so acetonitrile is selected as the solvent for the next reaction condition screening.

1.2 Effect of photocatalyst on reaction

After confirming the use of acetonitrile as the reaction solvent, Eosin B (Eosin B), tetrabromofluorescein (EY), rose bengal (RB), rhodamine, methylene blue, fac-Ir(ppy) ₃ , Effects of photocatalysts such as Ru(bpy) ₃ Cl ₂ ·6H ₂ O, Ru(phen) ₃ Cl ₂ , Ir(ppy) ₂ dtbbpy PF ₆ and Ir(dFCF ₃ ppy) ₂ (dtbbpy)PF ₆ on the reaction, the results See Table 2.

Table 2 Screening of different types of photocatalysts

Preparation method: sequentially add 0.2mmol of 1a, 0.6mmol of 2, photocatalyst (2mol%) and 2mL of acetonitrile into a test tube, and stir under a blue LED light for 24 hours at room temperature and in an air atmosphere.

In the experiment, when fac-Ir(ppy) ₃ , methylene blue, Ru(bpy) ₃ Cl ₂ ·6H ₂ O and Ru(phen) ₃ Cl ₂ were used as photocatalysts, the raw materials did not react completely, and other photocatalysts could react Among them, RB is the photocatalyst with the highest yield, reaching 61%. Therefore, acetonitrile was selected as the solvent, and RB was used as the photocatalyst to continue optimizing the reaction conditions.

1.3 Effect of the amount of photocatalyst on the reaction

After determining the use of acetonitrile as the reaction solvent and RB as the photocatalyst, the influence of the amount of photocatalyst input on the reaction was studied, and then the amount of photocatalyst was screened. The results are shown in Table 3.

Table 3 Screening of the amount of photocatalyst

Preparation method: add 0.2mmol of 1a, 0.6mmol of 2, RB and 2mL of acetonitrile into a test tube in turn, and stir under a blue LED light for 24 hours at room temperature and in an air atmosphere.

After screening the input amount of photocatalyst, it is found that when the input amount of RB increases to 5mol%, the yield can be increased to 64%.

In summary, we obtained that the optimal condition of this reaction is 0.2mmol of 1a, 0.6mmol of 2, RB (5mol%), dissolved in 2mL of acetonitrile, placed in blue LED light at room temperature and in an air atmosphere, and reacted for 24h. The yield of 3a was 64%.

Under the optimal conditions screened, the specific steps for preparing trifluoromethylated 2,4-quinolinedione compounds in the present invention are as follows:

Add N-o-cyanoarylacrylamide compound (0.2mmol), sodium trifluoromethylsulfinate (0.6mmol), RB (5mol%) and acetonitrile (2mL) successively into a 10mL test tube, then, room temperature, Under the condition of an air atmosphere, it was placed under the irradiation of a blue LED lamp and stirred for 24 hours. After the completion of the reaction was monitored by TLC, it was directly concentrated with a rotary evaporator, and then separated by silica gel column chromatography (ethyl acetate-petroleum ether system), and then the target product was obtained. product.

2. Substrate expansion

Under the optimal conditions screened, according to the above method, using raw materials N-methyl-N-(2-cyano-4-chlorophenyl)-2-methacrylamide (1b), N-methyl- N-(2-cyano-3-chlorophenyl)-2-methacrylamide (1c), N-methyl-N-(2-cyano-3-bromophenyl)-2-methylpropene Amide (1d) was tested, and the corresponding products 3b, 3c, and 3d were successfully obtained.

3. Structure and data characterization of products 3a, 3b, 3c, 3d

1,3-Dimethyl-3-(2,2,2-trifluoroethyl)-2,4-quinolinedione (3a)

Pale yellow solid (yield: 64%, separated by column chromatography eluent: petroleum ether/ethyl acetate=20/1); ¹ H NMR (300MHz, CDCl ₃ ) δ8.08 (d, J=7.7Hz, 1H), 7.67(t, J=7.6Hz, 1H), 7.22(t, J=10.1Hz, 2H), 3.50(s, 3H), 3.07(q, J=10.1Hz, 2H), 1.50(s, 3H); ¹⁹ F NMR (282MHz, CDCl ₃ ) δ-60.64(s).

6-Chloro-1,3-dimethyl-3-(2,2,2-trifluoroethyl)-2,4-quinolinedione (3b)

Off-white solid (yield: 73%, column chromatography eluent: petroleum ether/ethyl acetate=20/1); ¹ H NMR (300MHz, CDCl ₃ ) δ8.02(s, 1H), 7.61( d, J＝8.8Hz, 1H), 7.15(d, J＝8.8Hz, 1H), 3.48(s, 3H), 3.05(q, J＝10.1Hz, 2H), 1.49(s, 3H); ¹⁹ F NMR(282MHz, CDCl ₃ )δ-60.65(s).

5-Chloro-1,3-dimethyl-3-(2,2,2-trifluoroethyl)-2,4-quinolinedione (3c)

Yellow solid (yield: 60%, separated by column chromatography eluent: petroleum ether/ethyl acetate=20/1); ¹ H NMR (300MHz, CDCl ₃ ) δ7.50(t, J=8.2Hz, 1H ),7.24(dd,J=11.6,3.6Hz,1H),7.14(d,J=8.4Hz,1H),3.48(s,3H),3.09–2.93(m,2H),1.49(s,3H) ; ¹⁹ F NMR (282MHz, CDCl ₃ ) δ-59.17(s).

5-Bromo-1,3-dimethyl-3-(2,2,2-trifluoroethyl)-2,4-quinolinedione (3d)

Off-white solid (yield: 33%, column chromatography eluent: petroleum ether/ethyl acetate = 20/1); ¹ H NMR (300MHz, CDCl ₃ ) δ7.49 (d, J = 7.9Hz, 1H), 7.41(t, J=8.1Hz, 1H), 7.19(d, J=8.2Hz, 1H), 3.48(s, 3H), 3.02(q, J=10.3Hz, 2H), 1.50(s, 3H); ¹⁹ F NMR (282MHz, CDCl ₃ ) δ-59.09(s).

It can be seen from the above structural characterization that the target product can be obtained by the method provided in the present application.

Although the embodiment of the present invention has been disclosed as above, it is not limited to the use listed in the specification and implementation, it can be applied to various fields suitable for the present invention, and it can be easily understood by those skilled in the art Therefore, the invention is not limited to the specific details and embodiments shown and described herein without departing from the general concept defined by the claims and their equivalents.

Claims (4)

1. The preparation method of trifluoromethylated 2,4-quinolinedione compound, is characterized in that, comprises: Add N-o-cyanoaryl acrylamide compounds, sodium trifluoromethyl sulfinate, photocatalyst Rose Bengal and solvent acetonitrile into the reactor, then stir the reaction at room temperature, air atmosphere, and blue light irradiation conditions, After the reaction is complete, concentrate, and then separate by silica gel column chromatography to obtain trifluoromethylated 2,4-quinolinedione compounds; wherein, the N-o-cyanoaryl acrylamide compound is N-methyl Base-N-(2-cyanophenyl)-2-methacrylamide, N-methyl-N-(2-cyano-4-chlorophenyl)-2-methacrylamide, N-methyl -N-(2-cyano-3-chlorophenyl)-2-methacrylamide or N-methyl-N-(2-cyano-3-bromophenyl)-2-methacrylamide . 2. The preparation method of trifluoromethylated 2,4-quinolinedione compounds as claimed in claim 1, characterized in that the stirring reaction time is 24h. 3. the preparation method of trifluoromethylated 2,4-quinoline diketone compound as claimed in claim 1, is characterized in that, N-o-cyanoaryl acrylamide compound and trifluoromethylsulfinic acid The feeding molar ratio of sodium nitrate is 1:3. 4. trifluoromethylation 2 as claimed in claim 1, the preparation method of 4-quinoline diketone compound is characterized in that, the molar ratio of N-o-cyanoaryl acrylamide compound and photocatalyst is 1:0.05.