CN108774169B - 8-hydroxyquinoline compound and preparation method thereof - Google Patents

Abstract

The invention discloses an 8-hydroxyquinoline compound and a preparation method thereof. The structural formula of the 8-hydroxyquinoline compound is as follows:

; Wherein, R ¹ and R ² are independently selected from alkane, cycloalkane, phenyl, substituted phenyl or heterocyclic aromatic hydrocarbon; in substituted phenyl, the substituent is independently selected from alkyl, alkoxy, hydroxyl, halogen and any one or two or more combinations in the ester group; the preparation method is as follows: in the air atmosphere, the uniform mixing reaction system of 2-aminophenol, aldehyde, alkyne, catalyst and organic solvent is placed under the condition of 60-110 ℃ The reaction is carried out for 0.5-4h, and the reaction solution after the reaction is post-treated to obtain the target product 8-hydroxyquinoline compound. The present invention adopts a multi-component one-pot method, and the source of raw materials is simple and quick, and the amount of catalyst is low, which greatly reduces environmental costs. ; The operation is simple, the yield is high and the substrate universality is wide, which improves and enriches the construction of the molecular library of 8-hydroxyquinoline compounds.

Description

A kind of 8-hydroxyquinoline compound and preparation method thereof

technical field

The invention belongs to the technical field of organic synthesis, in particular to an 8-hydroxyquinoline compound and a preparation method thereof.

Background technique

8-Hydroxyquinoline compounds are important intermediates in organic synthesis and are widely used in chemistry, pharmacy and medicine. As excellent metal ion chelators, 8-hydroxyquinoline compounds have been widely used in metallurgical industry and analytical chemistry for chemical analysis of metal elements, extraction of metal ions, photometric analysis and metal anticorrosion; due to 8-hydroxyquinoline and Most of the derivatives have biological activity and are the raw materials for the synthesis of important drugs such as Kexielining and halogenated quinoline anti-amebic drugs, and are also widely used in the pharmaceutical industry; 8-hydroxyquinoline is directly used for disinfection Its halogenated derivatives, nitrates and N-oxides are the raw materials for the synthesis of drugs, and also serve as intermediates for the synthesis of pesticides, dyes and other functional materials; 8-hydroxyquinoline is bonded to the polymer resin, making it high Molecularization has broad application prospects in analysis, environment and materials, as well as electroluminescence, conductive polymers, etc.

Therefore, the research and development of synthetic methods for these compounds has attracted the attention of many people. Four methods have been reported in the literature, including quinoline sulfonation base fusion, chloroquinoline hydrolysis, aminoquinoline hydrolysis and Skraup synthesis.

But these methods have the following problems, method (1): the sulfonation alkali melting process needs a large amount of acid and alkali, and the amount of waste water is large, and produces serious pollution to the environment; Method (2): the required raw material 8-chloroquinoline is made of o-chloroaniline Obtained, but the toxicity of o-chloroaniline is relatively large, and the corrosiveness of chlorine-containing organic matter alkali hydrolysis is also very large; Method (3): the required raw material 8-aminoquinoline is reduced by 8-nitroquinoline, but the quinoline In the mixed acid nitration process, two isomers of 5-nitroquinoline and 8-nitroquinoline are obtained and are not easily separated; method (4): co-heating with o-aminophenol, concentrated sulfuric acid, glycerol and o-nitrophenol to obtain 8 -Hydroxyquinoline, this method needs to be carried out at high temperature, and the pyrolysis of glycerol produces tar to pollute the environment.

Undoubtedly, it is necessary to develop a method for synthesizing 8-hydroxyquinolines with high efficiency, wide source of raw materials, simple operation and environmental friendliness.

SUMMARY OF THE INVENTION

In view of the problems existing in the prior art, the present invention provides an 8-hydroxyquinoline compound and a preparation method thereof. The raw material source is simple and convenient, the operation is simple, the reaction is continuous, the atom economy is economical, and the environment-friendly multi-component one-pot method A method for tandem synthesis of 8-hydroxyquinoline compounds.

In order to solve the above-mentioned technical problems, the present invention adopts the following technical solutions:

An 8-hydroxyquinoline compound, the structural formula is as follows:

Wherein, R ¹ and R ² are each independently selected from alkane, cycloalkane, phenyl, substituted phenyl or heterocyclic aromatic hydrocarbon; the substituent in substituted phenyl is independently selected from alkyl, alkoxy, hydroxyl, halogen and Any one or a combination of two or more of the ester groups; the number of the substituents is one or more; the position of the substituents is the ortho position, the meta position or the para position.

The preparation method of the 8-hydroxyquinoline compound, the steps are as follows: in an air atmosphere, the uniform mixing reaction system of 2-aminophenol, aldehyde, alkyne, catalyst and organic solvent is reacted under the condition of 60-110 DEG C for 0.5 -4h, the reaction solution after the reaction is post-treated to obtain the target product 8-hydroxyquinoline compound.

The structure of the 2-aminophenol is shown in the formula (I), the structure of the aldehyde is shown in the formula (II), and the structure of the alkyne is shown in the formula (III),

Wherein, in formula (II) or formula (III), R ¹ and R ² are each independently selected from alkane, cycloalkane, phenyl, substituted phenyl or heterocyclic aromatic hydrocarbon; the substituent in substituted phenyl is independently selected from Any one or a combination of two or more of alkyl, alkoxy, hydroxyl, halogen and ester groups; the number of the substituents is one or more; the positions of the substituents are ortho, Interposition or paraposition.

The molar ratio of the 2-aminophenol, aldehyde and alkyne is (1.1-1.5):1:(1.2-2).

The catalyst includes a transition metal catalyst and a Bronsted acid catalyst; the transition metal catalyst includes one of silver trifluoromethanesulfonate, copper trifluoromethanesulfonate, and gold chloride; the Bronsted acid catalyst includes One of glacial acetic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.

The molar ratio of the transition metal catalyst to the aldehyde is 0.5-5:100; the molar ratio of the Bronsted acid catalyst to the aldehyde is 2-4:1.

The organic solvent is one of toluene, 1,2-dichloroethane, acetonitrile, methanol, and 1,4-dioxane.

The post-processing method of the reaction solution is as follows: after the reaction is completed, the solvent is evaporated under reduced pressure, washed with an alkaline solution, extracted with ethyl acetate or dichloromethane, and then separated and purified by column chromatography, using petroleum ether/ethyl acetate as eluent, gradient elution to obtain the 8-hydroxyquinoline compound.

Beneficial effects of the present invention: the present invention adopts a multi-component one-pot method, the source of raw materials is simple and quick, the amount of catalyst is low, and the environmental cost is greatly reduced; the operation is simple, the yield is high, and the substrate universality is wide, which is perfect and enriched. Construction of a molecular library of 8-hydroxyquinoline compounds. The beneficial effects of the invention are achieved through the synergistic catalysis of transition metals and Bronsted acids. Specifically, 2-aminophenol and aromatic or aliphatic aldehydes generate imine intermediates under the action of Bronsted acid. At the same time, transition metals activate terminal alkynes to generate metal-alkyne reactive intermediates with nucleophilic properties. Further, under the action of Bronsted acid, the nucleophilic addition-cyclization-oxidation tandem process of metal-alkyne active intermediates to activated imines finally generates 8-hydroxyquinoline compounds. The addition of Bronsted acid is beneficial to the formation of imine intermediates, and the introduction of transition metals facilitates the formation of metal-alkyne active intermediates. The synergistic catalytic effect of the two is beneficial to the rapid construction of 8-hydroxyquinoline skeleton.

Description of drawings

Fig. 1 is the single crystal diffraction pattern of 8-hydroxyquinoline compound 4g;

Fig. 2 is the single crystal diffraction pattern of 8-hydroxyquinoline compound 4i;

Fig. 3 is the nuclear magnetic resonance H spectrum of 8-hydroxyquinoline compound 4v;

Fig. 4 is the nuclear magnetic resonance C spectrum of 8-hydroxyquinoline compound 4v;

Fig. 5 is the nuclear magnetic resonance H spectrum of 8-hydroxyquinoline compound 4x;

Fig. 6 is the nuclear magnetic resonance C spectrum of 8-hydroxyquinoline compound 4x.

Detailed ways

The present invention will be further described below with reference to specific embodiments. It should be understood that the following examples are only used to illustrate the present invention rather than to limit the scope of the present invention, and those skilled in the art can make some non-essential improvements and adjustments according to the content of the above invention.

Example 1

The synthetic method of the present embodiment 8-hydroxyquinoline compound 4a is as follows:

To the dichloroethane (4 mL) solution containing AgOTf (0.5 mol%) were added o-aminophenol (1.1 mmol), benzaldehyde (1 mmol) and phenylacetylene (1.2 mmol) in turn, and after stirring at room temperature, trifluoroacetic acid was added. (4 mmol), the temperature was raised to 80°C for reaction. TLC monitored the reaction to complete, after adding 20 mL of dichloromethane, washed with water, dried over anhydrous sodium sulfate, and separated by column chromatography (PE/EA=20:1 as eluent) to obtain 280 mg of pale yellow solid powder with a yield of 94%.

¹ H NMR (600MHz, CDCl ₃ ) δ 8.16-8.20(m, 2H), 7.85(s, 1H), 7.46-7.58(m, 8H), 7.37-7.40(m, 2H), 7.21(d, J =8.7Hz, 1H)ppm; ¹³ C NMR (150MHz, CDCl ₃ ) δ 152.0, 150.2, 147.3, 136.4, 136.2, 135.8, 127.2, 127.1, 126.9, 126.5, 126.1, 125.8, 125.0, 124.8, 123.2, 123.6 ,117.5,113.6,107.6ppm.

Example 2

The synthetic method of the present embodiment 8-hydroxyquinoline compound 4b is as follows:

To the toluene (4 mL) solution containing AgOTf (0.5 mol%) was added o-aminophenol (1.2 mmol), p-methylbenzaldehyde (1 mmol) and phenylacetylene (1.3 mmol) in turn, and after stirring at room temperature, trifluoroacetic acid was added. (3 mmol), the temperature was raised to 80°C for reaction. Followed by TLC dot plate until the reaction was complete, concentrated to remove toluene, added 20 mL of dichloromethane, washed with water, dried with anhydrous sodium sulfate, and separated by column chromatography (PE/EA=20:1 as eluent) to obtain 286 mg of pale yellow solid , the yield is 92%.

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.09 (d, J=8.2 Hz, 2H), 7.84 (s, 1H), 7.55 (ddd, J=22.1, 11.4, 4.4 Hz, 5H), 7.33-7.39 ( m, 4H), 7.20 (dd, J=6.1, 2.6 Hz, 1H), 2.45 (s, 3H) ppm; ¹³ C NMR (150 MHz, CDCl ₃ ) δ 153.4, 151.4, 148.5, 138.8, 137.5, 137.3, 134.9, 128.7,128.6,128.4,128.3,127.6,127.5,126.4,126.2,126.1,124.8,118.7,114.9,108.8,20.3ppm.

Example 3

The synthetic method of the present embodiment 8-hydroxyquinoline compound 4c is as follows:

To a solution of AgOTf (1 mol%) in dioxane (4 mL) was added o-aminophenol (1.1 mmol), 2,4,6-trimethylbenzaldehyde (1 mmol) and phenylacetylene (1.5 mmol) in sequence at room temperature. After stirring uniformly, trifluoroacetic acid (1 mmol) was added, and the temperature was raised to 110°C for reaction. Followed by TLC dot plate until the reaction was complete, concentrated to remove dioxane, added 20 mL of dichloromethane, washed with water, dried over anhydrous sodium sulfate, and separated by column chromatography (PE/EA=15:1 as the eluent) to obtain pale 298 mg of yellow solid, yield 88%.

¹ H NMR (600MHz, CDCl ₃ ) δ 7.55-7.58(m, 2H), 7.53(t, J=7.3Hz, 2H), 7.47-7.51(m, 2H), 7.41-7.45(m, 1H), 7.35(s,1H), 7.19-7.22(m,1H), 7.01(s,2H), 2.37(s,3H), 2.11(s,6H)ppm; ^13C NMR(150MHz,CDCl3)δ156.6,151.5, 147.9,137.0,136.9,134.8,128.5,127.5,127.5,127.4 126.4,124.4,108.7,20.1,19.3ppm.

Example 4

The synthetic method of the present embodiment 8-hydroxyquinoline compound 4d is as follows:

To the dichloroethane (4 mL) solution containing AgOTf (0.5 mol%) was added o-aminophenol (1.1 mmol), p-bromobenzaldehyde (1 mmol) and phenylacetylene (1.2 mmol) in turn. Fluoroacetic acid (2 mmol) was heated to 70°C for reaction. Followed by TLC dot plate until the reaction was complete, after adding 20 mL of dichloromethane, washed with water, dried with anhydrous sodium sulfate, and separated by column chromatography (PE/EA=20:1 as eluent) to obtain 360 mg of pale yellow solid, yield 96% .

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.06 (d, J=8.3 Hz, 2H), 7.81 (s, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.55 (d, J=5.4 Hz) , 5H), 7.40 (d, J=6.0 Hz, 2H), 7.21 (d, J=2.4 Hz, 1 H) ppm; ¹³ CNMR (150 MHz, CDCl ₃ ) δ 153.2, 152.5, 150.0, 138.6, 138.1, 137.6, 132.3 ,132.1,129.5,129.3,129.0,128.9,127.8,127.7,126.1,124.2,119.5,116.1,110.2ppm.

Example 5

The synthetic method of the present embodiment 8-hydroxyquinoline compound 4e is as follows:

To the dichloroethane (4 mL) solution containing AgOTf (0.5 mol%) was added o-aminophenol (1.1 mmol), p-bromobenzaldehyde (1 mmol) and phenylacetylene (1.2 mmol) in turn. Fluoroacetic acid (2 mmol) was heated to 70°C for reaction. Followed by TLC dot plate until the reaction was complete, after adding 20 mL of dichloromethane, washed with water, dried with anhydrous sodium sulfate, and separated by column chromatography (PE/EA=20:1 as eluent) to obtain 355 mg of pale yellow solid, yield 95% .

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 8.34 (t, J=1.6 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.81 (s, 1H), 7.61 (d, J=8.0Hz, 1H), 7.55-7.57 (m, 3H), 7.50-7.540 (m, 1H), 7.40 (dd, J=8.8, 6.2Hz, 3H), 7.23 (dd, J=6.0 , 2.7 Hz, 1H) ppm; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 152.8, 152.6, 150.1, 140.8, 138.6, 138.1, 132.5, 130.4, 129.5, 128.7, 127.8, 126.2, 125.9, 123.2, 119.7, 116.1 ppm.

Example 6

The synthetic method of the present embodiment 8-hydroxyquinoline compound 4f is as follows:

To the dichloroethane (4 mL) solution containing AgOTf (0.5 mol%) was added o-aminophenol (1.1 mmol), p-bromobenzaldehyde (1 mmol) and phenylacetylene (1.2 mmol) in turn. Fluoroacetic acid (2 mmol) was heated to 70°C for reaction. Followed by TLC dot plate until the reaction was complete, after adding 20 mL of dichloromethane, washed with water, dried over anhydrous sodium sulfate, and separated by column chromatography (PE/EA=20:1 as eluent) to obtain 350 mg of pale yellow solid, yield 95% .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.72-7.75 (m, 2H), 7.69 (dd, J=7.6, 1.6 Hz, 1H), 7.57-7.61 (m, 2H), 7.49-7.55 (m, 3H) ),7.42-7.49(m,3H),7.32(td,J=7.8,1.7Hz,1H),7.22(dd,J=7.1,1.5Hz,1H)ppm.

Example 7

The synthetic method of the present embodiment 8-hydroxyquinoline compound 4g is as follows:

To the dioxane (4mL) solution containing AgOTf (1mol%) was added o-aminophenol (1.2mmol), p-bromobenzaldehyde (1mmol) and phenylacetylene (1.5mmol) in turn, after stirring at room temperature, trifluoro Acetic acid (4 mmol), warmed to 100 °C and reacted. Followed by TLC dot plate until the reaction was complete, concentrated to remove dioxane, added 20 mL of dichloromethane, washed with water, dried over anhydrous sodium sulfate, and separated by column chromatography (PE/EA=15:1 as the eluent) to obtain pale 307 mg of yellow solid, yield 86%.

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.25 (d, J=8.3 Hz, 2H), 8.19 (d, J=8.4 Hz, 2H), 7.88 (s, 1H), 7.55 (m, 5H), 7.41 (d, J=6.5Hz, 2H), 7.23 (dd, J=6.1, 2.5Hz, 1H), 3.97 (s, 3H) ppm; ¹³ CNMR (100 MHz, CDCl ₃ ) δ 166.8, 153.1, 152.6, 150.0, 142.8 ,138.6,138.0,130.9,130.1,129.5(s),128.7,128.6,128.0,127.3,126.3,119.9,116.1,110.3,52.3ppm.

Example 8

The synthetic method of the present embodiment 8-hydroxyquinoline compound 4h is as follows:

Add o-aminophenol (1.5 mmol), isovaleraldehyde (1 mmol) and phenylacetylene (2 mmol) to the dichloroethane (4 mL) solution containing AgOTf (2 mol %) in turn, and after stirring at room temperature, trifluoroacetic acid ( 4 mmol), the temperature was raised to 80 °C for the reaction. Followed by TLC dot plate until the reaction was complete, after adding 20 mL of dichloromethane, washed with water, dried with anhydrous sodium sulfate, and separated by column chromatography (PE/EA=30:1 as eluent) to obtain 252 mg of pale yellow solid, yield 86% .

¹ H NMR (600MHz, CDCl ₃ ) δ 7.46-7.52(m, 5H), 7.32-37(m, 2H), 7.23(s, 1H), 7.15(d, J=7.0Hz, 1H), 2.85( d, J=7.2Hz, 2H), 2.27 (dt, J=13.5, 6.7Hz, 1H), 1.00 (d, J=6.6Hz, 6H) ppm; ¹³ C NMR (151MHz, CDCl ₃ ) δ 158.8, 151.4, 148.2, 137.6, 137.5, 128.9, 127.8, 127.7, 125.9, 124.7, 122.4, 47.1, 29.2, 28.5, 21.9ppm.

Adopting the technical scheme of the present invention, the synthesized 8-hydroxyquinoline compounds are as follows:

The foregoing has shown and described the basic principles and main features of the present invention, as well as the advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above-mentioned embodiments, and the descriptions in the above-mentioned embodiments and the description are only to illustrate the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have Various changes and modifications fall within the scope of the claimed invention. The claimed scope of the present invention is defined by the appended claims and their equivalents.

Claims (3)

1. a preparation method of an 8-hydroxyquinoline compound, is characterized in that the steps are as follows: in an air atmosphere, the uniform mixing reaction system of 2-aminophenol, aldehyde, alkyne, catalyst and organic solvent is placed at a temperature of 60-110 ℃. The reaction is carried out for 0.5-4h under the conditions, and the reaction solution after the reaction is post-treated to obtain the target product 8-hydroxyquinoline compound, and the structural formula is as follows:

; The structure of the 2-aminophenol is shown in the formula (I), the structure of the aldehyde is shown in the formula (II), and the structure of the alkyne is shown in the formula (III),

; Wherein, R ¹ and R ² are each independently selected from alkane, cycloalkane, phenyl, substituted phenyl or heterocyclic aromatic hydrocarbon; the substituent in substituted phenyl is independently selected from alkyl, alkoxy, hydroxyl, halogen and Any one or a combination of two or more ester groups; the number of the substituents is one or more; the position of the substituents is ortho, meta or para; The molar ratio of the 2-aminophenol, aldehyde and alkyne is (1.1-1.5): 1: (1.2-2); Described catalyzer adopts silver trifluoromethanesulfonate and trifluoroacetic acid, and the mol ratio of described silver trifluoromethanesulfonate and aldehyde is (0.5-5): 100; The mol ratio of described trifluoroacetic acid and aldehyde is (2 -4): 1. 2. the preparation method of 8-hydroxyquinoline compounds according to claim 1, is characterized in that: described organic solvent is toluene, 1,2-dichloroethane, acetonitrile, methanol, 1,4-dioxygen One of the six rings. 3. the preparation method of 8-hydroxyquinoline compound according to claim 1, is characterized in that: the method for described reaction solution aftertreatment is: after reaction finishes, decompression evaporates solvent, washes with alkaline solution, Extraction with ethyl acetate or dichloromethane, and separation and purification by column chromatography, using petroleum ether/ethyl acetate as eluent, and gradient elution to obtain the 8-hydroxyquinoline compound.

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