A method for constructing benzo[3,2-a]quinoline salt using electrochemical oxidative coupling reaction

Abstract

The present invention relates to a method for synthesizing a benzoxazol[3,2-a]quinoline salt using an electrochemical oxidative coupling reaction. This method uses p-toluene disulfide and 2-bromoquinoline as reaction raw materials, successfully constructing the benzoxazol[3,2-a]quinoline salt compound through a two-step arylation and electrochemical oxidative coupling reaction. This method features readily available raw materials, concise synthesis steps, mild reaction conditions, and a simple operating process.

Description

Technical Field

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

[0002] N-heterocyclic compounds such as benzothiazole represent an attractive skeletal structure in materials science and biomedicine. Among them, benzo[3,2-a]quinolinium salt is an unnatural alkaloid with a wide range of biological activities. The positive charge on the nitrogen atom helps stabilize the complex formed with DNA, giving it excellent antitumor activity. Related literature has also reported that benzo[3,2-a]quinolinium salt and its derivatives are potential anticancer drugs. Traditional synthesis methods for benzo[3,2-a]quinolinium salt primarily use 2-methylbenzothiazole as a raw material. The reaction often requires high reaction temperatures and the addition of an equivalent amount of oxidant or toxic mercury reagent. The reaction steps are cumbersome and the reaction efficiency is low. Common synthetic routes are 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 benzoxazo[3,2-a]quinoline salt synthesized by the present invention has the following structural formula:

[0007]

[0008] This invention synthesizes benzo[3,2-a]quinoline salt through 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 easily 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 benzoxazol[3,2-a]quinolate compound using an electrochemical oxidative coupling reaction. This method uses p-toluene disulfide and 2-bromoquinoline as raw materials, successfully constructing the benzoxazol[3,2-a]quinolate compound through a two-step arylation and electrochemical oxidative coupling reaction. This method features readily available raw materials, concise synthetic steps, mild reaction conditions, and a simple operating procedure.

[0010] The technical solutions of the present invention are as follows.

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

[0012]

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

[0014] (1) Compound 1 (p-toluene disulfide) was placed in a container, and compound 2 (2-bromoquinoline) and sodium hydroxide were added. Dimethyl sulfoxide was used as a solvent, and the mixture was stirred at 120 degrees Celsius for 24 hours. TLC (thin layer chromatography) was used to track and detect the reaction until the end. The mixture was filtered, extracted, separated and purified to obtain compound 3 (2-(p-tolylthio)quinoline), thus completing the arylation process.

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

[0016] In the above method, the reaction vessel 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 existing technology, 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, the reaction conditions are mild, and it 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 benzoxazo[3,2-a]quinoline salt obtained in Example 2-12;

[0023] Figure 4 is the carbon NMR 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] To a dry, sealed tube, 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. The tube was then covered with a nitrogen-filled balloon and stirred at 120°C for 24 hours. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, diluted with 30 ml of ethyl acetate, and extracted with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. Compound 3 (2-(p-tolylthio)quinoline) was then isolated and purified by column chromatography to yield 72% yield.

[0028] The structural characterization data of compound 3 (2-(p-tolylthio)quinoline) obtained in Example 1 are as follows: (See 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 deduced based on the above data as follows:

[0032]

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

[0034] Example 2

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

[0036] In a 25 mL two-necked Schreck reaction tube, 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 were added. 5 mL of acetonitrile was added as the solvent. A nitrogen balloon was placed over the tube, and a carbon rod was used as the anode and nickel foam as the cathode. The reaction was stirred at 3 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and the nitrogen was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then separated and purified by column chromatography to obtain the compound benzo[3,2-a]quinoline salt in a 65% yield.

[0037] Example 3

[0038] To a 25 mL two-necked Schreck reaction tube, 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 were added. 5 mL of acetonitrile was added as the solvent. A nitrogen balloon was placed over the tube, and the reaction was stirred at 3 mA using a carbon rod as the anode and nickel foam as the cathode. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon removed, and the nitrogen gas slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then separated and purified by column chromatography to obtain the compound benzo[3,2-a]quinoline salt in a 71% yield.

[0039] Example 4

[0040] In a 25 mL two-necked Schreck reaction tube, 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 were added. 5 mL of acetonitrile was added as the solvent. A nitrogen balloon was placed over the tube, and a carbon rod was used as the anode and nickel foam as the cathode. The reaction was stirred at 3 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and the nitrogen was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then separated and purified by column chromatography to obtain the compound benzo[3,2-a]quinoline salt in a 75% yield.

[0041] Example 5

[0042] In a 25 mL two-necked Schreck reaction tube, 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 were added. 5 mL of acetonitrile was added as the solvent. A nitrogen balloon was placed over the tube, and a carbon rod was used as the anode and nickel foam as the cathode. The reaction was stirred at 3 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and the nitrogen was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then separated and purified by column chromatography to obtain the compound benzo[3,2-a]quinoline salt in a 45% yield.

[0043] Example 6

[0044] In a 25 mL two-necked Shrek reaction tube, 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 were added. 5 mL of acetonitrile was added as the solvent. A nitrogen balloon was placed over the tube, and a carbon rod was used as the anode and nickel foam as the cathode. The reaction was stirred at 3 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and the nitrogen was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then separated and purified by column chromatography to obtain the compound benzo[3,2-a]quinoline salt in a 63% yield.

[0045] Example 7

[0046] In a 25 mL two-necked Schreck reaction tube, 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 were added. 5 mL of acetonitrile was added as the solvent. A nitrogen balloon was placed over the tube, and a carbon rod was used as the anode and nickel foam as the cathode. The reaction was stirred at 3 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and the nitrogen was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then separated and purified by column chromatography to obtain the compound benzo[3,2-a]quinoline salt in a 51% yield.

[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 benzoxazo[3,2-a]quinoline salt by electrochemical oxidative coupling reaction, characterized in that: The benzoxazo[3,2-a]quinoline salt is prepared by two steps of arylation and electrochemical oxidative coupling reaction of compound 1 and compound 2; compound 1 is p-toluene disulfide, and compound 2 is 2-bromoquinoline; the synthesis route is as follows: ， The specific steps are as follows: (1) Compound 1 is placed in a container, compound 2 and sodium hydroxide are added, dimethyl sulfoxide is used as a solvent, and the mixture is stirred at 120°C for 24 hours. TLC (thin layer chromatography) is used to monitor the reaction until the end of the reaction. Compound 3 is then filtered, extracted, separated, and purified to achieve the arylation process. (2) Compound 3 is placed in a glass two-necked Schreck reaction tube, and an electrolyte, catalyst, tetrafluoroboric acid and 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 purified by column chromatography to obtain benzo[3,2-a]quinoline salt; the catalyst is palladium acetate or palladium chloride or palladium trifluoroacetate or bistriphenylphosphine palladium dichloride; the electrolyte is an ammonium salt or lithium perchlorate.

2. The method for constructing a benzoxazo[3,2-a]quinoline salt by electrochemical oxidative coupling reaction according to claim 1, characterized in that: The ammonium salt is tetrabutylammonium hexafluorophosphate or tetraethylammonium tetrafluoroborate.

3. The method for constructing a benzoxazo[3,2-a]quinoline salt by electrochemical oxidative coupling reaction according to claim 1, characterized in that: The solvent in the specific step (2) is acetonitrile.

4. The method for constructing a benzoxazo[3,2-a]quinoline salt by electrochemical oxidative coupling reaction according to claim 1, characterized in that: The reaction temperature in the specific step (2) is room temperature.

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