阅读说明：本技术 2-芳酰基喹啉衍生物的合成方法 (Synthesis method of 2-aroylquinoline derivative ) 是由 张兴国 康田梦 张小红 涂海勇 于 2021-09-01 设计创作，主要内容包括：本发明涉及一种2-芳酰基喹啉衍生物的合成方法,包括下列步骤：以2-溴苯胺和芳基环丁醇为反应底物,氯化钯为催化剂,三环己基膦为配体,碳酸铯作碱,超干甲苯作溶剂,在110 ～(o)C氮气保护下搅拌反应12小时,然后以四丁基碘化铵为相转移催化剂,在醋酸和过硫酸钾条件下,甲苯作溶剂于90℃下搅拌反应16小时。具有对反应条件要求相对低,条件温和,操作步骤简单,原料简单易得,大大降低了对环境的污染等优势。(The invention relates to a synthetic method of a 2-aroyl quinoline derivative, which comprises the following steps: taking 2-bromoaniline and aryl cyclobutanol as reaction substrates, palladium chloride as a catalyst, tricyclohexylphosphine as a ligand, cesium carbonate as an alkali and ultra-dry toluene as a solvent, and reacting at 110 DEG o Stirring and reacting for 12 hours under the protection of nitrogen, then stirring and reacting for 16 hours at 90 ℃ by taking tetrabutyl ammonium iodide as a phase transfer catalyst and toluene as a solvent under the conditions of acetic acid and potassium persulfate. The method has the advantages of relatively low requirement on reaction conditions, mild conditions, simple operation steps, simple and easily obtained raw materials, greatly reduced environmental pollution and the like.)

1. A method for synthesizing 2-aroylquinoline derivatives comprises the following steps: taking 2-bromoaniline and aryl cyclobutanol as reaction substrates, palladium chloride as a catalyst, tricyclohexylphosphine as a ligand, cesium carbonate as an alkali and ultra-dry toluene as a solvent, stirring and reacting for 12 hours at 110 ℃ under the protection of nitrogen, then taking tetrabutylammonium iodide as a phase transfer catalyst, stirring and reacting for 16 hours at 90 ℃ under the conditions of acetic acid and potassium persulfate, wherein the chemical reaction formula is as follows:

the-Ar is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorphenyl, 5-chlorphenyl and 2-naphthyl;

the R is one of a hydrogen atom or a phenyl;

the-R' is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorphenyl, 3- (trifluoromethyl) phenyl, 2-thienyl and 2-naphthyl.

2. The method of synthesizing a 2-aroylquinoline derivative according to claim 1, wherein: cooling to room temperature after the reaction is finished, washing by using a saturated sodium chloride solution, extracting by using ethyl acetate, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, purifying by using a flash column chromatography, eluting by using eluent ethyl acetate and petroleum ether, and collecting a target product for concentrating under reduced pressure.

Technical Field

The invention relates to a synthetic method of a 2-aroyl quinoline derivative.

Background

Quinoline derivatives have a wide range of biological activities, and substituted quinoline derivatives can be used as inhibitors of NTPBase8 with potent and selective properties (Bioorganic. Chemistry.2021, 115, 105240). For example, 6-dimethylamino-1-methylquinoline as a fluorescent probe with a parent structure can be used for the specific detection of beta amyloid and the early diagnosis of Alzheimer's disease, and has important guiding significance for the development of Alzheimer's disease diagnosis and treatment probes (CN 112920113A). More recently, quinoline derivatives have been used in third generation photovoltaic cells and in biomedical applicationsThe material is widely applied in the field of science and is an excellent material for preparing organic light-emitting diodes (J Mater Sci: Mater Electron.2021, 32, 18451-18465). The acyl hydrazine quinoline derivative has better bacteriostatic activity and is expected to become a potential bactericide for plant fungal diseases (J. Agric. Food Chem. 2021, 69, 8347-8357). The classical methods for the synthesis of quinoline rings are the various well-known reactions, such as Skraup, Doebner-von Miller et al. However, by these synthetic methods, multi-functionalized quinoline derivatives are often not obtained. Meanwhile, these methods have great disadvantages such as severe reaction conditions, complicated acidic medium and product separation steps, etc. Therefore, a method for synthesizing polysubstituted quinoline derivatives, which is environmentally friendly, efficient and economical in atom, needs to be found. Therefore, the invention provides a novel method for synthesizing the quinoline ring, which has the advantages of mild condition, simple and convenient operation and high substrate universality.

Object of the Invention

Aiming at the defects existing at the present stage, the invention provides a method for obtaining a 2-aroylquinoline derivative by using 2-bromoaniline and aryl cyclobutanol as reaction raw materials through metal catalytic coupling cyclization and oxidation rearrangement reaction and a one-pot method; has the advantages of simplicity, high efficiency, simple and convenient operation, no pollution and the like.

In order to achieve the purpose, the invention adopts the technical scheme that: a method for synthesizing 2-aroylquinoline derivatives comprises the following steps: taking 2-bromoaniline and aryl cyclobutanol as reaction substrates, palladium chloride as a catalyst, tricyclohexylphosphine as a ligand, cesium carbonate as an alkali and ultra-dry toluene as a solvent, stirring and reacting for 12 hours at 110 ℃ under the protection of nitrogen, then taking tetrabutylammonium iodide as a phase transfer catalyst, stirring and reacting for 16 hours at 90 ℃ under the conditions of acetic acid and potassium persulfate, wherein the chemical reaction formula is as follows:

the-Ar is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorphenyl, 5-chlorphenyl and 2-naphthyl;

the R is one of a hydrogen atom or a phenyl;

the-R' is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorphenyl, 3- (trifluoromethyl) phenyl, 2-thienyl and 2-naphthyl.

The preparation method adopted by the invention is that the 2-aroylquinoline compound is obtained by the 2-bromoaniline and the aryl cyclobutanol through a one-pot method, the technological process is simple and convenient to operate, safe and pollution-free, no special instrument or mode is needed, and the preparation method is very suitable for operation of people in the field.

The method can directly synthesize the target product, the yield can reach 75 percent to the maximum, the process flow is greatly simplified, and the yield is good; in addition, the waste solution is less in the reaction process, and other polluted gases and liquid are not discharged, so that the method reduces the discharge of the waste solution, and has the advantages of protecting the environment and ensuring the health of operators; in addition, a series of 2-aroylquinoline derivatives can be prepared, and the method has better substrate universality. Therefore, the invention fills the blank of the method for preparing the quinoline derivative at the present stage, promotes the development of the nitrogen-containing heterocyclic organisms and provides a powerful guarantee for developing the medicament containing the quinoline derivative.

The mechanism of the invention is as follows: firstly, 2-bromoaniline and zero-valent palladium are oxidized and added to obtain an intermediate A, and then ligand exchange is carried out to combine with cyclobutanol anions to generate palladium alkoxide B. Subsequently, the ring opening is eliminated by the beta-carbon atom to give the alkyl palladium intermediate C. And the intermediate C is reduced to eliminate gamma-arylated ketone D and zero-valent palladium. Finally, the gamma-arylated ketone D is subjected to intramolecular dehydration condensation to obtain an intermediate E. The free radical acetoxylation of the intermediate provides an intermediate F, tetrahydroquinoline G is obtained through hydrolysis and further condensation, and finally the target product is provided through dehydrogenation and oxidation.

Detailed Description

A synthetic method of 2-aroylquinoline derivatives comprises the following steps of taking 2-bromoaniline and aryl cyclobutanol as reaction substrates, palladium chloride as a catalyst, tricyclohexylphosphine as a ligand, cesium carbonate as an alkali and ultra-dry toluene as a solvent, carrying out stirring reaction for 12 hours at 110 ℃ under the protection of nitrogen, then taking tetrabutylammonium iodide as a phase transfer catalyst, carrying out stirring reaction for 16 hours at 90 ℃ under the conditions of acetic acid and potassium persulfate, and taking the toluene as a solvent, wherein the chemical reaction formula is as follows:

the-Ar is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorphenyl, 5-chlorphenyl and 2-naphthyl;

the R is one of a hydrogen atom or a phenyl;

the-R' is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorphenyl, 3- (trifluoromethyl) phenyl, 2-thienyl and 2-naphthyl.

After the reaction, the reaction mixture was washed with a saturated sodium chloride solution, extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue. Eluting the residue with silica gel column with eluent prepared from ethyl acetate and petroleum ether at volume ratio (v: v), collecting eluate according to actual gradient, detecting by TLC, mixing eluates containing target product, removing solvent by rotary evaporator, and vacuum drying to obtain target product.

The first embodiment is as follows: 17 mg (0.1 mmol) of 2-bromoaniline, 16.28 mg (0.11 mmol) of 1-phenylcyclobutanol, 0.885 mg (0.005 mmol) of palladium chloride, 2.8 mg (0.005 mmol) of tricyclohexylphosphine, 65.15 mg (0.2 mmol) of cesium carbonate, 4MS (50.0 mg) and ultra-dry toluene (1 mL) were added. In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as a solvent. The reaction was stirred at 90 ℃ for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and saturated with waterWashed with sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether in a volume ratio of 1:30 as eluent to give 17 mg of phenyl (quinolin-2-yl) methanone in 73% yield.¹H NMR (500 MHz, CDCl₃) δ 8.35 (d, J = 8.5 Hz, 1H), 8.25-8.23 (m, 2H), 8.21-8.20 (m, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.80-7.77 (m, 1H), 7.68-7.61(m, 2H), 7.53-7.50 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 193.7, 154.7, 146.8, 137.0, 136.2, 133.0, 131.4, 130.5, 130.0, 128.9, 128.4, 128.1, 127.6, 120.8。

The second embodiment is as follows: 18.5 mg (0.1 mmol) of 4-methyl-2-bromoaniline, 16.28 mg (0.11 mmol) of 1-phenylcyclobutanol, 0.885 mg (0.005 mmol) of palladium chloride, 2.8 mg (0.005 mmol) of tricyclohexylphosphine, 65.15 mg (0.2 mmol) of cesium carbonate, 4MS (50.0 mg) and ultra-dry toluene (1 mL) were added. In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as a solvent. The reaction was stirred at 90 ℃ for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether in a volume ratio of 1:30 as eluent to give 18.5 mg of (6-methylquinolin-2-yl) (phenyl) methanone in 75% yield.¹H NMR (400 MHz, CDCl₃) δ 8.24-8.23 (m, 3H), 8.10-8.08 (m, 2H), 7.66 (s, 1H), 7.62-7.60 (m, 2H), 7.51 (t, J = 7.2 Hz, 2H), 2.58 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 193.8, 153.8, 145.3, 138.7, 136.29, 136.27, 132.9, 132.4, 131.4, 130.2, 129.0, 128.1, 126.4, 120.8, 21.8。

The third concrete embodiment: 20.0 mg (0.1 mmol) of 4-methoxy-2-bromoaniline, 16.28 mg (0.11 mmol) of 1-phenylcyclobutanol, 0.885 mg (0.005 mmol) of chloridizationPalladium, 2.8 mg (0.005 mmol) tricyclohexylphosphine, 65.15 mg (0.2 mmol) cesium carbonate, 4MS (50.0 mg) and ultra dry toluene (1 mL). In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as a solvent. The reaction was stirred at 90 ℃ for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether in a volume ratio of 1:30 as eluent to give 16.8 mg of (6-methoxyquinolin-2-yl) (phenyl) methanone in 64% yield.¹H NMR (400 MHz, CDCl₃) δ 8.23-8.20 (m, 3H), 8.13-8.07 (m, 2H), 7.62-7.60 (m, 1H), 7.53-7.51 (m, 2H), 7.44-7.41 (m, 1H), 7.14 (s, 1H), 3.98 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 193.7, 159.4, 152.3, 142.8, 136.4, 135.5, 132.8, 132.0, 131.4, 130.3, 128.0, 123.1, 121.3, 104.8, 55.6。

The fourth concrete embodiment: 20.5 mg (0.1 mmol) of 4-chloro-2-bromo-aniline, 16.28 mg (0.11 mmol) of 1-phenylcyclobutanol, 0.885 mg (0.005 mmol) of palladium chloride, 2.8 mg (0.005 mmol) of tricyclohexylphosphine, 65.15 mg (0.2 mmol) of cesium carbonate, 4MS (50.0 mg) and ultra-dry toluene (1 mL) were added. In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as a solvent. The reaction was stirred at 90 ℃ for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether in a volume ratio of 1:30 as eluent to give 18.2 mg of (6-chloroquinolin-2-yl) (phenyl) methanone in 68% yield.¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 7.6 Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 1.2 Hz, 1H), 7.73 (dd, J = 8.8, 1.6 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 193.4, 154.8, 145.1, 136.2, 136.0, 134.4, 133.2, 132.1, 131.4, 131.2, 129.5, 128.2, 126.3, 121.7。

The fifth concrete embodiment: 20.5 mg (0.1 mmol) of 5-chloro-2-bromo-aniline, 16.28 mg (0.11 mmol) of 1-phenylcyclobutanol, 0.885 mg (0.005 mmol) of palladium chloride, 2.8 mg (0.005 mmol) of tricyclohexylphosphine, 65.15 mg (0.2 mmol) of cesium carbonate, 4MS (50.0 mg) and ultra-dry toluene (1 mL) were added. In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as a solvent. The reaction was stirred at 90 ℃ for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether in a volume ratio of 1:30 as eluent to give (7-chloroquinolin-2-yl) (phenyl) methanone 15.0 mg, 56% yield.¹H NMR (400 MHz, CDCl₃) δ 8.34 (d, J = 8.4 Hz, 1H), 8.22-8.21 (m, 3H), 8.11 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.66-7.60 (m, 2H), 7.52 (t, J = 8.0 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 193.4, 155.5, 147.0, 137.0, 136.1, 135.9, 133.2, 131.4, 129.44, 129.38, 128.8, 128.2, 127.2, 121.0。

The sixth specific embodiment: 22.1 mg (0.1 mmol) of 3-bromonaphthalen-2-amine, 16.28 mg (0.11 mmol) of 1-phenylcyclobutan-1-ol, 0.885 mg (0.005 mmol) of palladium chloride, 2.8 mg (0.005 mmol) of tricyclohexylphosphine, 65.15 mg (0.2 mmol) of cesium carbonate, 4MS (50.0 mg) and ultra-dry toluene (1 mL) were added. In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as solventIn (1). The reaction was stirred at 90 ℃ for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Eluting with eluent prepared from ethyl acetate and petroleum ether at a volume ratio of 1:30, and purifying the residue by flash column chromatography to obtain benzo [ h%]Quinolin-2-yl (phenyl) methanone 11.3 mg, 40% yield.¹H NMR (400 MHz, CDCl₃) δ 9.17-9.15 (m, 1H), 8.39-8.30 (m, 4H), 7.95-7.91 (m, 2H), 7.78-7.65 (m, 4H), 7.57 (t, J = 7.2 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 193.6, 152.8, 145.0, 136.73, 136.70, 133.8, 132.7, 131.8, 131.6, 130.0, 128.6, 128.0, 127.9, 127.7, 127.6, 124.9, 124.8, 121.9。

The seventh specific embodiment: 17 mg (0.1 mmol) of 2-bromoaniline, 17.82 mg (0.11 mmol) of 1- (p-tolyl) cyclobutane-1-ol, 0.885 mg (0.005 mmol) of palladium chloride, 2.8 mg (0.005 mmol) of tricyclohexylphosphine, 65.15 mg (0.2 mmol) of cesium carbonate, 4MS (50.0 mg) and ultra-dry toluene (1 mL) were added. In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as a solvent. The reaction was stirred at 90 ℃ for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether in an eluent prepared at a volume ratio of 1:30 to give quinolin-2-yl (p-tolyl) methanone 14.1 mg, 57% yield.¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.0 Hz, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 193.4, 155.0, 146.7, 143.9, 137.0, 133.5, 131.5, 130.4, 130.0, 128.9, 128.8, 128.2, 127.6, 120.8, 21.7。

The eighth embodiment: 17 mg (0.1 mmol) of 2-bromoaniline, 19.58 mg (0.22 mmol) of 1- (4-methoxyphenyl) cyclobutan-1-ol, 0.885 mg (0.005 mmol) of palladium chloride, 2.8 mg (0.005 mmol) of tricyclohexylphosphine, 65.15 mg (0.2 mmol) of cesium carbonate, 4MS (50.0 mg) and ultra-dry toluene (1 mL) were added. In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as a solvent. The reaction was stirred at 90 ℃ for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether in a volume ratio of 1:30 eluent to give 17.1 mg of (4-methoxyphenyl) (quinolin-2-yl) methanone in 65% yield.¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J = 8.4 Hz, 1H), 8.30-8.27 (m, 2H), 8.21 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.80-7.76 m, 1H), 7.67-7.63 (m, 1H), 7.01-6.98 (m, 2H), 3.90 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 192.2, 163.7, 155.3, 146.6, 137.0, 133.8, 130.3, 130.0, 128.9, 128.7, 128.1, 127.6, 120.8, 113.5, 55.4。

The specific embodiment is nine: 17 mg (0.1 mmol) of 2-bromoaniline, 20.02 mg (0.22 mmol) of 1- (4-chlorophenyl) cyclobutan-1-ol, 0.885 mg (0.005 mmol) of palladium chloride, 2.8 mg (0.005 mmol) of tricyclohexylphosphine, 65.15 mg (0.2 mmol) of cesium carbonate, 4MS (50.0 mg) and ultra-dry toluene (1 mL) were added. In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as a solvent. The reaction was stirred at 90 ℃ for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Using ethyl acetate and petroleum ether in a volume ratio of 130 elution and purification of the residue by flash column chromatography gave 16.5 mg of (4-chlorophenyl) (quinolin-2-yl) methanone in 62% yield.¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 8.0 Hz, 2H), 8.19 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 192.3, 154.2, 146.6, 139.5, 137.2, 134.5, 132.9, 130.5, 130.2, 129.0, 128.6, 128.4, 127.7, 120.7。

The specific embodiment ten: 17 mg (0.1 mmol) of 2-bromoaniline, 23.76 mg (0.22 mmol) of 1- (3- (trifluoromethyl) phenyl) cyclobutan-1-ol, 0.885 mg (0.005 mmol) of palladium chloride, 2.8 mg (0.005 mmol) of tricyclohexylphosphine, 65.15 mg (0.2 mmol) of cesium carbonate, 4MS (50.0 mg) and ultra-dry toluene (1 mL) were added. In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as a solvent. The reaction was stirred at 90 ℃ for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether in a volume ratio of 1:30 as eluent to afford quinolin-2-yl (3- (trifluoromethyl) phenyl) methanone 16.9 mg, 56% yield.¹H NMR (400 MHz, CDCl₃₎ δ 8.62 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.21-8.17 (m, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.81 (t, J = 7.2 Hz, 1H), 7.71-7.64 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 192.0, 153.6, 146.7, 137.4, 136.8, 134.6, 130.60 (2J = 32.6 Hz), 130.55, 130.3, 129.2 (3J = 3.5 Hz), 129.1, 128.8, 128.6, 128.5 (3J = 3.8 Hz), 127.7, 123.9 (1J = 270.7 Hz), 120.6。

The first specific embodiment: 17 mg (0.1 mmol) of 2-bromoaniline, 16.94 mg (0.22 mmol)) 1- (thien-2-yl) cyclobutane-1-ol, 0.885 mg (0.005 mmol) of palladium chloride, 2.8 mg (0.005 mmol) of tricyclohexylphosphine, 65.15 mg (0.2 mmol) of cesium carbonate, 4MS (50.0 mg) and ultra-dry toluene (1 mL). In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as a solvent. The reaction was stirred at 90 ℃ for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether in a volume ratio of 1:30 as eluent to give quinolin-2-yl (thiophen-2-yl) methanone 9.6 mg in 40% yield.¹H NMR (400 MHz, CDCl₃) δ 8.51-8.50 (m, 1H), 8.35-8.25 (m, 3H), 7.91 (d, J = 8.0 Hz, 1H), 7.84-7.80 (m, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.23 (t, J = 4.0 Hz, 1H). ¹³C NMR (100 MHz, CDCl3) δ 183.6, 153.4, 146.7, 139.7, 137.2, 136.8, 130.3, 130.1, 129.3, 128.6, 127.7, 127.5, 119.8。

The specific example twelve: 17 mg (0.1 mmol) of 2-bromoaniline, 21.78 mg (0.22 mmol) of 1- (naphthalen-2-yl) cyclobutane-1-ol, 0.885 mg (0.005 mmol) of palladium chloride, 2.8 mg (0.005 mmol) of tricyclohexylphosphine, 65.15 mg (0.2 mmol) of cesium carbonate, 4MS (50.0 mg) and ultra-dry toluene (1 mL) were added. In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as a solvent. The reaction was stirred at 90 ℃ for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether in a volume ratio of 1:30 as eluent to afford naphthalen-2-yl (quinolin-2-yl) methanone 14.4 mg in 51% yield.¹H NMR (400 MHz, CDCl₃) δ 8.82 (s, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.97-7.90 (m, 4H), 7.81 (t, J = 7.2 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 193.7, 155.0, 146.8, 137.1, 135.6, 134.1, 133.4, 132.4, 130.5, 130.1, 129.9, 128.9, 128.5, 128.4, 127.9, 127.72, 127.66, 126.5, 126.4, 120.9。

The specific example thirteen: 17 mg (0.1 mmol) of 2-bromoaniline, 24.64 mg (0.22 mmol) of 1, 3-diphenylcyclobutane-1-ol, 0.885 mg (0.005 mmol) of palladium chloride, 2.8 mg (0.005 mmol) of tricyclohexylphosphine, 65.15 mg (0.2 mmol) of cesium carbonate, 4MS (50.0 mg) and ultra-dry toluene (1 mL) were added. In N₂Stirring under atmosphere, heating at 110 deg.C, and finishing reaction after 12 h. 7.38 mg (0.02 mmol) of tetrabutylammonium iodide, 108 mg (0.4 mmol) of potassium persulfate and 18 mg (0.3 mmol) of acetic acid were then added to 1ml of toluene as a solvent. The reaction was stirred at 90 ℃ for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether in a volume ratio of 1:30 as eluent to give 7.7 mg of phenyl (3-phenylquinolin-2-yl) methanone in 25% yield.¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.79 (t, J = 8.0 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.42-7.39 (m, 4H), 7.34-7.29 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 195.1, 156.3, 146.0, 137.7, 137.2, 136.2, 134.0, 133.5, 130.5, 130.1, 129.7, 129.0, 128.6, 128.4, 128.1, 128.0, 127.9, 127.7。

In the embodiment of the invention, 2-bromoaniline and aryl cyclobutanol are used as reaction substrates, palladium chloride is used as a catalyst, tricyclohexylphosphine is used as a ligand, cesium carbonate is used as alkali, and toluene is used as a solvent, and the reaction is carried out at 110 DEG^oStirring and reacting for 12 hours under the protection of nitrogen, and then carrying out phase transfer catalysis on tetrabutylammonium iodideThe agent is prepared by taking toluene as a solvent to stir and react for 16 hours at 90 ℃ under the conditions of acetic acid and potassium persulfate. Wherein examples one to six are variable substitutions of Ar in 2-bromoaniline by different substituents, and examples seven to twelve are variable substitutions of R' in aryl cyclobutanol by different substituents; example thirteen is the variation of R in aryl cyclobutanol.

According to the invention, the intermediate product does not need to be separated, the target product can be directly synthesized by simple raw materials, the process is simplified, the energy consumption is low, the waste solution discharge is reduced, the environmental pollution is reduced, and the yield reaches 75% at most; the above examples used a series of 2-aroylquinoline derivatives prepared by a one-pot method using a mixture of 2-bromoaniline and aryl cyclobutanol, which had some substrate versatility. The present invention is not limited to the above embodiments, and those skilled in the art can implement the present invention in other embodiments according to the disclosure of the present invention, or make simple changes or modifications on the design structure and idea of the present invention, and fall into the protection scope of the present invention.