Method for constructing phenyl azole [3, 2-a] quinoline salt by utilizing electrochemical oxidative coupling reaction

Abstract

The invention relates to a synthesis method for constructing a phenyl azole [3, 2-a] quinoline salt by using an electrochemical oxidative coupling reaction. According to the method, p-toluene disulfide and 2-bromoquinoline are taken as reaction raw materials, and the benzotriazole [3, 2-a] quinoline salt compound is successfully constructed through two steps of arylation and electrochemical oxidative coupling reaction. The method has the characteristics of simple and easily available raw materials, simple synthesis steps, mild reaction conditions and simple operation process.

Description

Technical Field

[0001] The invention relates to the technical fields of medicine, clinic, cell biology and the like, and in particular to a method for constructing a benzo[3,2-a]quinoline salt by utilizing an electrochemical oxidative coupling reaction. Background Art

[0002] Benzothiazole and other N-heterocyclic compounds are extremely attractive skeleton structures in the fields of materials science and biomedicine. Among them, benzo[3,2-a]quinoline salt is a non-natural alkaloid with a wide range of biological activities. The presence of positive charges on the nitrogen atom helps to stabilize the complex formed with DNA, giving it good anti-tumor activity. In addition, relevant literature has reported that benzo[3,2-a]quinoline salt and its derivatives are potential anticancer drugs. The traditional synthesis method of benzo[3,2-a]quinoline salt mainly uses 2-methylbenzothiazole as the raw material. The reaction process often requires the use of a higher reaction temperature, the addition of an equivalent amount of oxidant or toxic mercury reagent, and the reaction steps are cumbersome and the reaction efficiency is low. The commonly used synthesis route is as follows.

[0003]

[0004] In this research context, we proposed a method for constructing benzo[3,2-a]quinoline salts using an electrochemical oxidative coupling reaction. The synthetic route is as follows:

[0005]

[0006] The benzo[3,2-a]quinoline salt synthesized by the present invention has the following structural formula:

[0007]

[0008] The invention synthesizes benzo[3,2-a]quinoline salt by a two-step electrochemical oxidative coupling reaction, providing a novel synthetic route for the synthesis of this type of compound. The raw materials involved in this route are cheap and readily available, the reaction conditions are mild, and the reaction route is simple. Summary of the invention

[0009] The present invention relates to a method for synthesizing a benzo[3,2-a]quinoline salt compound by using an electrochemical oxidative coupling reaction. The method uses p-toluene disulfide and 2-bromoquinoline as reaction raw materials and successfully constructs a benzo[3,2-a]quinoline salt compound by two steps of arylation and electrochemical oxidative coupling reaction. The method has the characteristics of simple and easy-to-obtain raw materials, concise synthesis steps, mild reaction conditions, and simple operation process.

[0010] The technical solution of the present invention is as follows.

[0011] Benzazole [3,2-a] quinoline salt was synthesized by two-step electrochemical oxidative coupling reaction. The synthesis route is as follows:

[0012]

[0013] In the above method, the benzo[3,2-a]quinoline salt is prepared by two steps of arylation and electrochemical oxidative coupling reaction of compound 1 (p-toluene disulfide) and compound 2 (2-bromoquinoline); the specific steps are as follows:

[0014] (1) Compound 1 (p-toluene disulfide) is placed in a container, compound 2 (2-bromoquinoline) and sodium hydroxide are added, dimethyl sulfoxide is used as a solvent, and the mixture is stirred at 120 degrees Celsius for 24 hours. TLC (thin layer chromatography) is used to track and detect until the reaction is completed. Compound 3 (2-(p-tolylthio)quinoline) is obtained by filtration, extraction, separation and purification, thereby achieving an arylation process.

[0015] (2) Compound 3 (2-(p-tolylthio)quinoline) is placed in a two-necked Shrek reaction tube, an electrolyte, a catalyst, and a solvent are added, a balloon filled with nitrogen gas is placed on the tube, a carbon rod is used as an anode, and nickel foam is used as a cathode. The reaction is stirred at a current of 3 mA. After the reaction is completed, the balloon is removed, the reaction solution is filtered, and benzo[3,2-a]quinoline salt is purified by column chromatography; the catalyst is metal palladium; and the electrolyte is ammonium salt.

[0016] In the above method: the reaction container of the specific step (2) is a glass two-necked Shrek reaction tube; the metal palladium is palladium acetate, palladium chloride, palladium trifluoroacetate or bistriphenylphosphine palladium dichloride; and the electrolyte is tetrabutylammonium hexafluorophosphate, tetraethylammonium tetrafluoroborate or lithium perchlorate.

[0017] In the above method, the solvent in the specific step (2) is acetonitrile.

[0018] In the above method, the reaction temperature in the specific step (2) is room temperature.

[0019] Compared with the prior art, the advantages of the present invention are: the method has a novel synthesis method, and the benzo[3,2-a]quinoline salt is successfully synthesized by electrochemical oxidative coupling reaction. The reaction raw materials are simple and easy to obtain, and the reaction conditions are mild, which meets the development requirements of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of compound 3 (2-(p-tolylthio)quinoline) obtained in Example 1;

[0021] Figure 2 is the carbon NMR spectrum of compound 3 (2-(p-tolylthio)quinoline) obtained in Example 1;

[0022] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of the benzo[3,2-a]quinoline salt obtained in Example 2-12;

[0023] Figure 4 is the carbon nuclear magnetic resonance spectrum of the benzo[3,2-a]quinoline salt obtained in Example 2-12; DETAILED DESCRIPTION

[0024] The invention will be further described below through specific embodiments.

[0025] Example 1

[0026] Synthesis of Compound 3 (2-(p-tolylthio)quinoline)

[0027] 3 mmol of p-toluene disulfide, 5 mmol of 2-bromoquinoline, 7.5 mmol of sodium hydroxide and 5 ml of dimethyl sulfoxide were added to a dry sealed tube, covered with a balloon filled with nitrogen gas, and stirred at 120 degrees Celsius for 24 hours. After the reaction was completed by TLC (thin layer chromatography), the reaction solution was cooled to room temperature, the mixture was diluted with 30 ml of ethyl acetate, and saturated sodium chloride solution was added for extraction, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by vacuum rotary evaporation, and then separated and purified by column chromatography to obtain compound 3 (2-(p-tolylthio)quinoline) with a yield of 72%.

[0028] The structural characterization data of compound 3 (2-(p-tolylthio)quinoline) obtained in Example 1 are as follows: Figure 1 and Figure 2 )

[0029] 1 H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 8.5 Hz, 1H), 7.88 (dd, J = 8.7,2.6 Hz, 1H), 7.72-7.64 (m, 2H), 7.58 (dt, J = 8.3, 2.3 Hz, 2H), 7.45 (t, J =7.6 Hz, 1H), 7.29 (d, J = 7.2 Hz, 2H), 6.98 (dd, J = 8.7, 2.4 Hz, 1H), 2.45(d, J = 2.6 Hz, 3H).

[0030] 13C NMR (125 MHz, CDCl3) δ 162.28, 148.05, 139.63, 136.41, 135.37,130.51, 130.01, 128.31, 127.57, 127.17, 125.81, 125.69, 119.26, 21.35.

[0031] The structure of the obtained compound 3 (2-(p-tolylthio)quinoline) is inferred from the above data as follows:

[0032]

[0033] Compound 3 (2-(p-tolylthio)quinoline)quinoline)

[0034] Example 2

[0035] Synthesis of Benzazol[3,2-a]Quinoline Salt

[0036] In a 25 mL two-necked Shrek reaction tube, add 0.2 mmol of compound 3 (2-(p-tolylthio)quinoline), 0.01 mmol of palladium dichloride, 0.04 mmol of tetrabutylammonium hexafluorophosphate, and 0.4 mmol of tetrafluoroboric acid. Add 5 ml of acetonitrile as solvent, put on a balloon containing nitrogen, use a carbon rod as an anode, and nickel foam as a cathode, and stir the reaction under a current of 3 mA. After the reaction is completed by TLC (thin layer chromatography), the reaction solution is cooled to room temperature, the balloon is removed, and the nitrogen is slowly vented. The reaction solution is filtered, the filtrate is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound benzo[3,2-a]quinoline salt with a yield of 65%.

[0037] Example 3

[0038] In a 25 mL two-necked Shrek reaction tube, add 0.2 mmol of compound 3 (2-(p-tolylthio)quinoline), 0.01 mmol of palladium trifluoroacetate, 0.04 mmol of tetrabutylammonium hexafluorophosphate, and 0.4 mmol of tetrafluoroboric acid. Add 5 ml of acetonitrile as solvent, put on a balloon containing nitrogen, use a carbon rod as an anode, and nickel foam as a cathode, and stir the reaction under a current of 3 mA. After the reaction is completed by TLC (thin layer chromatography), the reaction solution is cooled to room temperature, the balloon is removed, and the nitrogen is slowly vented. The reaction solution is filtered, the filtrate is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound benzo[3,2-a]quinoline salt with a yield of 71%.

[0039] Example 4

[0040] In a 25 mL two-necked Shrek reaction tube, add 0.2 mmol of compound 3 (2-(p-tolylthio)quinoline), 0.01 mmol of palladium acetate, 0.04 mmol of tetrabutylammonium hexafluorophosphate, and 0.4 mmol of tetrafluoroboric acid. Add 5 ml of acetonitrile as solvent, put on a balloon containing nitrogen, use a carbon rod as an anode, and nickel foam as a cathode, and stir the reaction under a current of 3 mA. After the reaction is completed by TLC (thin layer chromatography), the reaction solution is cooled to room temperature, the balloon is removed, and the nitrogen is slowly vented. The reaction solution is filtered, the filtrate is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound benzo[3,2-a]quinoline salt with a yield of 75%.

[0041] Example 5

[0042] In a 25 mL two-necked Shrek reaction tube, add 0.2 mmol of compound 3 (2-(p-tolylthio)quinoline), 0.01 mmol of bistriphenylphosphine palladium dichloride, 0.04 mmol of tetrabutylammonium hexafluorophosphate, and 0.4 mmol of tetrafluoroboric acid. Add 5 ml of acetonitrile as solvent, put on a balloon containing nitrogen, use a carbon rod as an anode, and nickel foam as a cathode, and stir the reaction under a current of 3 mA. After the reaction is completed by TLC (thin layer chromatography), the reaction solution is cooled to room temperature, the balloon is removed, and the nitrogen is slowly vented. The reaction solution is filtered, the filtrate is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound benzo[3,2-a]quinoline salt with a yield of 45%.

[0043] Example 6

[0044] In a 25 mL two-necked Shrek reaction tube, add 0.2 mmol of compound 3 (2-(p-tolylthio)quinoline), 0.01 mmol of palladium acetate, 0.04 mmol of tetraethylammonium tetrafluoroborate, and 0.4 mmol of tetrafluoroboric acid. Add 5 ml of acetonitrile as solvent, put on a balloon containing nitrogen, use a carbon rod as an anode, and nickel foam as a cathode, and stir the reaction under a current of 3 mA. After the reaction is completed by TLC (thin layer chromatography), the reaction solution is cooled to room temperature, the balloon is removed, and the nitrogen is slowly vented. The reaction solution is filtered, the filtrate is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound benzo[3,2-a]quinoline salt with a yield of 63%.

[0045] Example 7

[0046] In a 25 mL two-necked Shrek reaction tube, add 0.2 mmol of compound 3 (2-(p-tolylthio)quinoline), 0.01 mmol of palladium acetate, 0.04 mmol of lithium perchlorate, and 0.4 mmol of tetrafluoroboric acid. Add 5 ml of acetonitrile as solvent, put on a balloon containing nitrogen, use a carbon rod as an anode, and nickel foam as a cathode, and stir the reaction under a current of 3 mA. After the reaction is completed by TLC (thin layer chromatography), the reaction solution is cooled to room temperature, the balloon is removed, and the nitrogen is slowly vented. The reaction solution is filtered, the filtrate is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound benzo[3,2-a]quinoline salt with a yield of 51%.

[0047] The structural characterization data of the benzo[3,2-a]quinoline salt obtained in Example 2-7 are as follows: (see Figure 3 and Figure 4 )

[0048] 1 H NMR (500 MHz, Methanol-d4) δ 9.44 (d, J = 8.9 Hz, 1H), 9.10 (s,1H), 8.86 (d, J = 9.0 Hz, 1H), 8.60 (d, J = 9.0 Hz, 1H), 8.49 (d, J = 8.0 Hz,1H), 8.38 (d, J = 8.3 Hz, 1H), 8.32 (t, J = 8.1 Hz, 1H), 8.08 (t, J = 7.7 Hz,1H), 7.85 (d, J = 8.4 Hz, 1H), 2.80 (s, 3H).

[0049] 13 C NMR (125 MHz, Methanol-d4) δ 141.14, 140.13, 139.61, 137.29,133.83, 130.96, 130.81, 129.15, 127.63, 126.54, 124.15, 119.79, 118.85,118.58, 20.64.

[0050] Based on the above data, the structure of the obtained benzo[3,2-a]quinoline salt is as follows:

[0051] .

Claims

1. A method for constructing a benzo[3,2-a]quinoline salt by electrochemical oxidative coupling reaction, characterized in that: The synthetic route is as follows: 。 2. A method for constructing benzo[3,2-a]quinoline salt by electrochemical oxidative coupling reaction according to claim 1, characterized in that: The benzo[3,2-a]quinoline salt is prepared by two steps of arylation and electrochemical oxidative coupling reaction of compound 1 (p-toluene disulfide) and compound 2 (2-bromoquinoline); the compound 1 is p-toluene disulfide, and the compound 2 is 2-bromoquinoline. The specific steps are as follows: (1) Compound 1 (p-toluene disulfide) is placed in a container, compound 2 (2-bromoquinoline) and sodium hydroxide are added, dimethyl sulfoxide is used as a solvent, and the mixture is stirred at 120 degrees Celsius for 24 hours. TLC (thin layer chromatography) is used to track and detect the reaction until the end of the reaction. Compound 3 (2-(p-tolylthio)quinoline) is obtained by filtration, extraction, separation and purification to achieve the arylation process; (2) Compound 3 (2-(p-tolylthio)quinoline) is placed in a two-necked Shrek reaction tube, an electrolyte, a catalyst, and a solvent are added, a balloon filled with nitrogen gas is placed on the tube, a carbon rod is used as an anode, and nickel foam is used as a cathode. The reaction is stirred at a current of 3 mA. After the reaction is completed, the balloon is removed, the reaction solution is filtered, and benzo[3,2-a]quinoline salt is purified by column chromatography; the catalyst is metal palladium; and the electrolyte is ammonium salt.

3. A method for constructing a benzo[3,2-a]quinoline salt by electrochemical oxidative coupling reaction according to claim 2, characterized in that: The reaction container of the specific step (2) is a glass two-necked Shrek reaction tube; the metal palladium is palladium acetate, palladium chloride, palladium trifluoroacetate or bistriphenylphosphine palladium dichloride; and the electrolyte is tetrabutylammonium hexafluorophosphate, tetraethylammonium tetrafluoroborate or lithium perchlorate.

4. A method for constructing benzo[3,2-a]quinoline salt by electrochemical oxidative coupling reaction according to claim 2, characterized in that: In the specific step (2), the solvent is acetonitrile.

5. A method for constructing benzo[3,2-a]quinoline salt by electrochemical oxidative coupling reaction according to claim 2, characterized in that: The reaction temperature in the specific step (2) is room temperature.

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