CN116655529A - Method for synthesizing 3-aryl quinoline compound by nickel catalysis - Google Patents

Method for synthesizing 3-aryl quinoline compound by nickel catalysis Download PDF

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CN116655529A
CN116655529A CN202310614019.4A CN202310614019A CN116655529A CN 116655529 A CN116655529 A CN 116655529A CN 202310614019 A CN202310614019 A CN 202310614019A CN 116655529 A CN116655529 A CN 116655529A
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reaction
quinoline
synthesizing
aryl
nickel
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邱仁华
张博
盛星浩
尹双凤
神户宣明
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Hunan University
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Hunan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/10—Aza-phenanthrenes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Abstract

We have developed a method of 3-arylquinolines. The method takes the imidate, the n-heptyl Grignard reagent and the iodobenzene as raw materials, and can realize the synthesis of 3-aryl quinoline compounds through nickel metal catalysis in a nitrogen environment. The method has the advantages of wide substrate range, mild reaction condition, higher target product yield, simple and convenient reaction operation, small reaction pollution and the like, and has certain feasibility for industrialized mass production.

Description

Method for synthesizing 3-aryl quinoline compound by nickel catalysis
Technical Field
The invention relates to a method for synthesizing 3-aryl quinoline compounds by nickel catalysis, in particular to a method for synthesizing 3-aryl quinoline compounds by nickel catalysis and a reagent in a format of n-heptyl by using an iodobenzene one-pot two-step method, belonging to the fields of organic chemistry and chemical industry.
Background
The substituted nitrogen heterocycle taking quinoline as the structural center is widely existed in artificial synthetic medicines and natural products, is an important pharmacophore, is widely existed in a plurality of bioactive molecules, and plays an irreplaceable role in disease treatment, such as antimalarial, antituberculosis, cancer treatment and the like.
In recent years, with the rapid increase of resource investment in the biomedical field and the new energy industry, related industries have put higher demands on the large-scale and efficient synthesis of bioactive compounds and novel functional molecules. The conventional synthesis method of the substituted nitrogen heterocyclic compound cannot meet the requirements of high efficiency and environmental protection, and in recent years, a new thought and a new method are provided for the convenient and efficient synthesis of the nitrogen-containing heterocyclic compound by activating and functional groups through the C-H bond catalyzed by transition metal, but a plurality of problems still need to be solved, such as the generation of more byproducts and the increase of production cost caused by the use of noble metal catalysts due to the excessively high reaction temperature. Therefore, developing a low-cost metal-catalyzed nitrogen-containing heterocyclic arylation process with mild conditions and rapid reaction is of great significance in the field of organic synthesis.
The synthesis method of the substituted quinoline compound which has been reported at present comprises the following steps: the palladium-catalyzed reaction of quinoline without a guide group and iodobenzene realizes the No. 3 arylation, and the guide group is introduced on the N atom of the quinoline to react with phenylboronic acid to realize the No. 3 arylation. However, the method for synthesizing the 3-aryl quinoline compound has the problems of high reaction temperature, long reaction time and the like because expensive transition metal and toxic ligand are needed in the reaction process. Therefore, it is important to develop a green and simple method for synthesizing 3-arylquinolines.
Disclosure of Invention
Aiming at the defects of the existing synthesis method, a method for preparing 3-aryl quinoline compounds is developed. The method takes the imidate, the n-heptyl Grignard reagent and the iodobenzene as raw materials, and can realize the synthesis of 3-aryl quinoline compounds through nickel metal catalysis in a nitrogen environment.
In order to achieve the above object, the present invention proposes the following technical scheme:
in the scheme, quinoline I, a format reagent II and iodobenzene III are used as raw materials, and two-step electrophilic addition and reduction elimination reactions are carried out under the condition of nitrogen through nickel catalysis, so that a 5, 8-difunctional substituted quinoline compound IV can be obtained.
As a preferable scheme, the quinoline compound I has a structure shown in a formula 1:
wherein R is various aliphatic hydrocarbon groups and halogen atoms.
As a preferred embodiment, the n-heptyl format reagent II has a structure represented by formula 2:
as a preferred embodiment, the iodobenzene III has a structure represented by formula 3:
wherein R' is aliphatic hydrocarbon group or various halogen atom substituents.
As a preferable scheme, the 3-aryl quinoline compound IV has a structure shown in a formula 4:
wherein R and R' are aliphatic hydrocarbon groups and various halogen atom substituents.
As a preferred embodiment, the molar amount of the n-heptyl formatting reagent is 1.5 times the molar amount of quinoline. The ratio of the formazan reagent is increased or decreased, which has a more obvious reduction on the yield of the target product, and when the ratio is 1.5 times, the yield of the reaction is optimal.
As a preferred embodiment, the molar amount of the iodobenzene is 1 to 2 times the molar amount of the quinoline. The yield of the target product is obviously improved by increasing the proportion of the iodobenzene. When the addition amount reaches or exceeds 2 times of quinoline, the yield of the target product of the reaction is not obviously improved.
As a preferred scheme, the solvent used in the reaction is diethylene glycol dimethyl ether.
The quinoline and n-heptyl format reagent of the invention adopts a specific reaction principle that two-step electrophilic addition and reduction elimination between iodobenzene are possible: initially, ni (COD) 2 Is reduced to a zero-valent Ni compound by a format reagent, and the zero-valent Ni compound is coordinated with quinoline to form an intermediate A. Then, n-heptyl grignard reagent and intermediate a nucleophilic add to produce intermediate B. And (3) performing electrophilic attack on the intermediate B by using iodobenzene, and then reducing and eliminating to obtain a target product.
Compared with the prior art, the technical scheme of the invention has the following advantages:
first, the process does not require precious metals and toxic ligands;
secondly, the method is realized in one pot and two steps, and has high atom utilization rate and extremely high selectivity;
third, the process yields up to 78% and is tolerant to a variety of functional groups;
fourth, the method is simple, mild, green and can effectively synthesize 3 aryl quinoline compounds;
fifth, the method has a certain feasibility for industrial mass production.
Drawings
FIG. 1 is a proposed method for the nickel-catalyzed synthesis of 3-phenylquinoline; FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of 3-phenylquinoline; FIG. 3 is a nuclear magnetic resonance carbon spectrum of 3-phenylquinoline.
Detailed Description
The foregoing features, advantages and objects of the invention will be apparent from the following more particular description of the invention, as illustrated in the accompanying drawings. In the above description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. The invention may be embodied in many other forms than described herein and similarly modified by those skilled in the art without departing from the spirit or scope of the invention, which is therefore not limited to the specific embodiments disclosed below.
The reaction materials and catalysts referred to in the following examples are commercially available reagents which are conventional in the market unless otherwise specified.
Condition optimization experiment: taking quinoline and n-heptyl magnesium bromide as an example to illustrate the synthesis of 3-phenylquinoline by iodobenzene, optimizing the conditions of reactant proportion, catalyst selection, solvent selection, reaction time, reaction temperature and the like, monitoring the reaction yield by a gas chromatograph, and obtaining the optimal reaction conditions, wherein the specific reaction under the optimal reaction conditions is as follows:
quinoline (25.8 mg,0.2 mmol), bis (1, 5-cyclooctadiene) nickel (5.5 mg,10 mol%) and 2mL of diethylene glycol dimethyl ether were weighed in a 10mL reaction tube equipped with a magnetic stirring bar in a glove box. The reaction tube was sealed with a polytetrafluoroethylene-lined screw cap and removed from the glove box, and n-heptyl magnesium bromide (0.6 ml,1.0m in tetrahydrofuran) was added dropwise to the reaction tube via syringe under nitrogen. The reaction was stirred at 30℃for 20 min. Iodobenzene (0.4 mmol) was then added to the reaction tube under nitrogen and the reaction stirred at 30 ℃ for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3X 3 mL), and the combined layers were dried over anhydrous sodium sulfate, followed by the addition of excess 1, 2-dichloro-4, 5-dicyanobenzoquinone (0.3 mmol,68.1 mg). Evaporating the solvent under vacuum, and performing column chromatography separation by using a solvent with a ratio of petroleum ether to ethyl acetate to obtain the target product 3-phenylquinoline, wherein the yield is 78%.
Project Differences from standard reaction conditions Gas chromatography yield
1 No difference 78％
2 No catalyst Trace reactions
3 Nickel triflate as catalyst 52％
4 Nickel 1, 3-bis (diphenylphosphinopropane) dichloride as catalyst 60％
5 Nickel fluoride is used as catalyst 59％
6 Bis (1, 5-cyclooctadiene) nickel in an amount of 5% 63％
7 The use level of the bis (1, 5-cyclooctadiene) nickel is 20 percent 78％
8 Using tetrahydrofuran as solvent 61％
9 Using1, 4-dioxane as solvent Trace amount of
10 Use of cyclopentyl methyl ether as solvent 55％
11 The reaction temperature in the first step is set to 60 DEG 73％
12 The reaction temperature in the first step is set to 100 DEG C 65％
13 The reaction temperature in the first step is set to 150 DEG C 51％
14 The reaction temperature in the second step is set to 60 DEG C 77％
15 The reaction temperature in the second step is set to 100 DEG C 50％
16 The reaction temperature in the second step is set to 150 DEG C Trace amount of
17 The reaction time of the first step is set to 20min 78％
18 The reaction time of the first step is set to be 1h 78％
19 The reaction time of the first step is set to 3h 75％
20 The reaction time of the first step is set to 8h 68％
21 The reaction time of the first step is set to 16h 60％
22 The reaction time of the second step is set to be 30min 66％
23 The reaction time of the second step is set to be 1h 41％
24 The reaction time of the second step is set to 8h 76％
25 The reaction time of the second step is set to 16h 72％
As can be seen from the above tables, the nickel catalysts and the amounts thereof used have a significant effect on the yield of the target product, and the reaction proceeds smoothly with various nickel catalysts, wherein the yield of the target product is highest with bis (1, 5-cyclooctadiene) nickel catalysis, and the target product is hardly obtained without the nickel catalyst. Wherein, when the nickel catalyst is used in an amount of 10%, the yield of the target product is highest.
As can be seen from the above tables, the reaction was smoothly carried out in most of the organic solvents, and the yield was highest when diethylene glycol dimethyl ether was used as the reaction solvent, whereas the reaction was smoothly carried out but the yield was low when tetrahydrofuran and cyclopentyl methyl ether were used as the solvents, and the objective product was hardly obtained when 1, 4-dioxane was used as the solvent. Diethylene glycol dimethyl ether is the reaction solvent for the best reaction.
As can be seen from the above tables in experimental groups 1 and 11 to 16, the reaction temperature affects the yield of the target product of the reaction, and when the reaction is performed in the first step, the reaction yield is lowered by increasing the temperature, and when the reaction temperature is 30 ℃, the reaction yield is highest; in the second step of the reaction, increasing the temperature decreases the yield of the reaction, which is highest at 30 degrees. The yield of the target product of the reaction is highest when the first step is 30 degrees and the second step is 30 degrees.
As can be seen from the above tables in experimental groups 1 and 17 to 25, the reaction time affects the yield of the target product of the reaction, and the prolonged time decreases the yield of the reaction at the first step of the reaction, and the yield is highest at 20 min. In the second step, the reaction yield is improved by extending the time, the reaction yield is highest when reaching 3 hours, and the reaction yield is reduced by continuing the extending time. In the first reaction step for 20min and in the second reaction step for 3h, the yield of the target product is highest.
The invention is further illustrated below in connection with specific preparation examples 1 to 8:
preparation example 1
Quinoline (25.8 mg,0.2 mmol), bis (1, 5-cyclooctadiene) nickel (5.5 mg,10 mol%) and 2mL of diethylene glycol dimethyl ether were weighed in a 10mL reaction tube equipped with a magnetic stirring bar in a glove box. The reaction tube was sealed with a polytetrafluoroethylene-lined screw cap and removed from the glove box, and n-heptyl magnesium bromide (0.6 ml,1.0m in tetrahydrofuran) was added dropwise to the reaction tube via syringe under nitrogen. The reaction was stirred at 30℃for 20 min. Iodobenzene (0.4 mmol) was then added to the reaction tube under nitrogen and the reaction stirred at 30 ℃ for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3X 3 mL), and the combined layers were dried over anhydrous sodium sulfate, followed by the addition of excess 1, 2-dichloro-4, 5-dicyanobenzoquinone (0.3 mmol,68.1 mg). Evaporating the solvent under vacuum, and performing column chromatography separation by using a solvent with a ratio of petroleum ether to ethyl acetate to obtain the target product 3-phenylquinoline, wherein the yield is 78%.
1 H NMR(400MHz,CDCl 3 )δ9.18(d,1H),8.28(d,1H),8.14(d,1H),7.87(m,1H),7.71(m,3H),7.60-7.50(m,3H),7.45-7.40(m,1H).
13 C NMR(101MHz,CDCl 3 )δ149.9,147.3,137.8,133.8,133.2,129.3,129.2,129.1,128.1,128.0,128.0,127.4,126.9.
Preparation example 2
Quinoline (25.8 mg,0.2 mmol), bis (1, 5-cyclooctadiene) nickel (5.5 mg,10 mol%) and 2mL of diethylene glycol dimethyl ether were weighed in a 10mL reaction tube equipped with a magnetic stirring bar in a glove box. The reaction tube was sealed with a polytetrafluoroethylene-lined screw cap and removed from the glove box, and n-heptyl magnesium bromide (0.6 ml,1.0m in tetrahydrofuran) was added dropwise to the reaction tube via syringe under nitrogen. The reaction was stirred at 30℃for 20 min. 2-methyl iodobenzene (0.4 mmol) was then added to the reaction tube under nitrogen and the reaction stirred at 30℃for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3X 3 mL), and the combined layers were dried over anhydrous sodium sulfate, followed by the addition of excess 1, 2-dichloro-4, 5-dicyanobenzoquinone (0.3 mmol,68.1 mg). Evaporating the solvent under vacuum, and performing column chromatography separation by using a solvent with a ratio of petroleum ether to ethyl acetate to obtain a target product 3- (o-methylphenyl) quinoline, wherein the yield is 70 percent.
1 H NMR(400MHz,CDCl 3 )δ8.93(d,J＝2.2Hz,1H),8.16(d,J＝8.5Hz,1H),8.08(d,J＝2.1Hz,1H),7.84(d,J＝8.1Hz,1H),7.73(m,1H),7.57(m,1H),7.39-7.27(m,4H),2.32(s,3H).
13 C NMR(101MHz,CDCl 3 )δ151.38,146.90,138.02,135.75,135.26,134.74,130.56,130.11,129.30,129.18,128.11,127.79,127.67,126.82,126.10,20.40.
Preparation example 3
Quinoline (25.8 mg,0.2 mmol), bis (1, 5-cyclooctadiene) nickel (5.5 mg,10 mol%) and 2mL of diethylene glycol dimethyl ether were weighed in a 10mL reaction tube equipped with a magnetic stirring bar in a glove box. The reaction tube was sealed with a polytetrafluoroethylene-lined screw cap and removed from the glove box, and n-heptyl magnesium bromide (0.6 ml,1.0m in tetrahydrofuran) was added dropwise to the reaction tube via syringe under nitrogen. The reaction was stirred at 30℃for 20 min. 3-methyl iodobenzene (0.4 mmol) was then added to the reaction tube under nitrogen and the reaction stirred at 30℃for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3X 3 mL), and the combined layers were dried over anhydrous sodium sulfate, followed by the addition of excess 1, 2-dichloro-4, 5-dicyanobenzoquinone (0.3 mmol,68.1 mg). Evaporating the solvent under vacuum, and performing column chromatography separation by using a solvent with a ratio of petroleum ether to ethyl acetate to obtain a target product 3- (m-methylphenyl) quinoline, wherein the yield is 75 percent.
1 H NMR(400MHz,CDCl 3 )δ9.17(d,J＝2.3Hz,1H),8.27(d,J＝2.2Hz,1H),8.14(d,J＝8.4Hz,1H),7.86(d,J＝8.2Hz,1H),7.74-7.67(m,1H),7.60-7.48(m,3H),7.40(t,J＝7.8Hz,1H),7.27-7.21(m,1H),2.46(s,3H).
13 C NMR(101MHz,CDCl 3 )δ149.95,147.24,138.81,137.78,133.91,133.12,129.25,129.15,129.02,128.81,128.10,127.99,127.93,126.90,124.48,21.52.
Preparation example 4
Quinoline (25.8 mg,0.2 mmol), bis (1, 5-cyclooctadiene) nickel (5.5 mg,10 mol%) and 2mL of diethylene glycol dimethyl ether were weighed in a 10mL reaction tube equipped with a magnetic stirring bar in a glove box. The reaction tube was sealed with a polytetrafluoroethylene-lined screw cap and removed from the glove box, and n-heptyl magnesium bromide (0.6 ml,1.0m in tetrahydrofuran) was added dropwise to the reaction tube via syringe under nitrogen. The reaction was stirred at 30℃for 20 min. 4-methyl iodobenzene (0.4 mmol) was then added to the reaction tube under nitrogen and the reaction stirred at 30℃for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3X 3 mL), and the combined layers were dried over anhydrous sodium sulfate, followed by the addition of excess 1, 2-dichloro-4, 5-dicyanobenzoquinone (0.3 mmol,68.1 mg). Evaporating the solvent under vacuum, and performing column chromatography separation by using a solvent with a ratio of petroleum ether to ethyl acetate to obtain the target product 3- (p-methylphenyl) quinoline, wherein the yield is 79 percent.
1 H NMR(400MHz,CDCl 3 )δ9.17(d,J＝2.3Hz,1H),8.26(d,J＝2.2Hz,1H),8.13(d,J＝8.4Hz,1H),7.85(d,J＝7.8Hz,1H),7.70(m,1H),7.62-7.52(m,3H),7.32(d,J＝7.9Hz,2H),2.42(s,3H).
13 C NMR(101MHz,CDCl 3 )δ149.87,147.14,137.99,134.88,133.70,132.74,129.84,129.13,128.02,127.88,127.17,126.87,21.13.
Preparation example 5
Quinoline (25.8 mg,0.2 mmol), bis (1, 5-cyclooctadiene) nickel (5.5 mg,10 mol%) and 2mL of diethylene glycol dimethyl ether were weighed in a 10mL reaction tube equipped with a magnetic stirring bar in a glove box. The reaction tube was sealed with a polytetrafluoroethylene-lined screw cap and removed from the glove box, and n-heptyl magnesium bromide (0.6 ml,1.0m in tetrahydrofuran) was added dropwise to the reaction tube via syringe under nitrogen. The reaction was stirred at 30℃for 20 min. 4-fluoroiodobenzene (0.4 mmol) was then added to the reaction tube under nitrogen and the reaction stirred at 30℃for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3X 3 mL), and the combined layers were dried over anhydrous sodium sulfate, followed by the addition of excess 1, 2-dichloro-4, 5-dicyanobenzoquinone (0.3 mmol,68.1 mg). Evaporating the solvent under vacuum, and performing column chromatography separation by using a solvent with a ratio of petroleum ether to ethyl acetate to obtain a target product 3- (4-fluorophenyl) quinoline, wherein the yield is 70 percent.
1 H NMR(400MHz,CDCl 3 )δ9.16(s,1H),8.28(d,J＝2.2Hz,1H),8.17(d,J＝8.4Hz,1H),7.90(d,J＝8.8Hz,1H),7.78-7.67(m,3H),7.61(m,1H),7.28-7.21(m,2H).
19 FNMR(376MHz,CDCl 3 )δ-114.08.
13 C NMR(101MHz,CDCl 3 )δ164.15,149.63,147.25,134.00,133.97,133.08,129.46,129.20,129.11,129.03,127.92,127.11,116.27,116.05.
Preparation example 6
Quinoline (25.8 mg,0.2 mmol), bis (1, 5-cyclooctadiene) nickel (5.5 mg,10 mol%) and 2mL of diethylene glycol dimethyl ether were weighed in a 10mL reaction tube equipped with a magnetic stirring bar in a glove box. The reaction tube was sealed with a polytetrafluoroethylene-lined screw cap and removed from the glove box, and n-heptyl magnesium bromide (0.6 ml,1.0m in tetrahydrofuran) was added dropwise to the reaction tube via syringe under nitrogen. The reaction was stirred at 30℃for 20 min. 4-chloroiodobenzene (0.4 mmol) was then added to the reaction tube under nitrogen and the reaction stirred at 30℃for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3X 3 mL), and the combined layers were dried over anhydrous sodium sulfate, followed by the addition of excess 1, 2-dichloro-4, 5-dicyanobenzoquinone (0.3 mmol,68.1 mg). Evaporating the solvent under vacuum, and performing column chromatography separation by using a solvent with a ratio of petroleum ether to ethyl acetate to obtain a target product 3- (4-chlorophenyl) quinoline, wherein the yield is 75 percent.
1 H NMR(400MHz,CDCl 3 )δ9.16(d,J＝2.3Hz,1H),8.29(d,J＝2.2Hz,1H),8.17(d,J＝8.5Hz,1H),7.90(d,J＝7.8Hz,1H),7.76(m,1H),7.70-7.58(m,3H),7.55-7.49(m,2H).
13 C NMR(101MHz,CDCl 3 )δ149.45,147.38,136.28,134.36,133.17,132.61,129.61,129.35,129.21,128.60,127.96,127.86,127.16.
Preparation example 7
Quinoline (25.8 mg,0.2 mmol), bis (1, 5-cyclooctadiene) nickel (5.5 mg,10 mol%) and 2mL of diethylene glycol dimethyl ether were weighed in a 10mL reaction tube equipped with a magnetic stirring bar in a glove box. The reaction tube was sealed with a polytetrafluoroethylene-lined screw cap and removed from the glove box, and n-heptyl magnesium bromide (0.6 ml,1.0m in tetrahydrofuran) was added dropwise to the reaction tube via syringe under nitrogen. The reaction was stirred at 30℃for 20 min. 4-bromoiodobenzene (0.4 mmol) was then added to the reaction tube under nitrogen and the reaction stirred at 30℃for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3X 3 mL), and the combined layers were dried over anhydrous sodium sulfate, followed by the addition of excess 1, 2-dichloro-4, 5-dicyanobenzoquinone (0.3 mmol,68.1 mg). Evaporating the solvent under vacuum, and performing column chromatography separation by using a solvent with a ratio of petroleum ether to ethyl acetate to obtain a target product 3- (4-bromophenyl) quinoline, wherein the yield is 75% as a white solid.
1 H NMR(400MHz,CDCl 3 )δ9.16(d,J＝2.3Hz,1H),8.29(d,J＝2.2Hz,1H),8.17(d,J＝8.5Hz,1H),7.90(d,J＝7.8Hz,1H),7.76(m,1H),7.70-7.58(m,3H),7.55-7.49(m,2H).
13 C NMR(101MHz,CDCl 3 )δ149.45,147.38,136.28,134.36,133.17,132.61,129.61,129.35,129.21,128.60,127.96,127.86,127.16.
Preparation example 8
Quinoline (25.8 mg,0.2 mmol), bis (1, 5-cyclooctadiene) nickel (5.5 mg,10 mol%) and 2mL of diethylene glycol dimethyl ether were weighed in a 10mL reaction tube equipped with a magnetic stirring bar in a glove box. The reaction tube was sealed with a polytetrafluoroethylene-lined screw cap and removed from the glove box, and n-heptyl magnesium bromide (0.6 ml,1.0m in tetrahydrofuran) was added dropwise to the reaction tube via syringe under nitrogen. The reaction was stirred at 30℃for 20 min. 4-iodobenzene (0.4 mmol) was then added to the reaction tube under nitrogen and the reaction stirred at 30℃for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3X 3 mL), and the combined layers were dried over anhydrous sodium sulfate, followed by the addition of excess 1, 2-dichloro-4, 5-dicyanobenzoquinone (0.3 mmol,68.1 mg). Evaporating the solvent under vacuum, and performing column chromatography separation by using a solvent with a ratio of petroleum ether to ethyl acetate to obtain a target product 3- (4-iodophenyl) quinoline, wherein the yield is 72% as a white solid.
1 H NMR(400MHz,CDCl 3 )δ9.15(d,J＝2.3Hz,1H),8.29(d,J＝2.1Hz,1H),8.16(d,J＝8.5Hz,1H),7.93-7.85(m,3H),7.76(m,1H),7.61(m,1H),7.49-7.43(m,2H).
13 C NMR(101MHz,CDCl 3 )δ149.33,147.44,138.26,137.33,133.11,132.69,129.64,129.23,129.11,127.97,127.85,127.17,94.09.
Preparation example 9
Quinoline (25.8 mg,0.2 mmol), bis (1, 5-cyclooctadiene) nickel (5.5 mg,10 mol%) and 2mL of diethylene glycol dimethyl ether were weighed in a 10mL reaction tube equipped with a magnetic stirring bar in a glove box. The reaction tube was sealed with a polytetrafluoroethylene-lined screw cap and removed from the glove box, and n-heptyl magnesium bromide (0.6 ml,1.0m in tetrahydrofuran) was added dropwise to the reaction tube via syringe under nitrogen. The reaction was stirred at 30℃for 20 min. 1-iodonaphthalene (0.4 mmol) was then added to the reaction tube under nitrogen and the reaction stirred at 30℃for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3X 3 mL), and the combined layers were dried over anhydrous sodium sulfate, followed by the addition of excess 1, 2-dichloro-4, 5-dicyanobenzoquinone (0.3 mmol,68.1 mg). Evaporating the solvent under vacuum, and performing column chromatography separation by using a solvent with a ratio of petroleum ether to ethyl acetate to obtain a target product 3- (naphthalene-1-yl) quinoline, wherein the yield is 69 percent.
1 H NMR(400MHz,CDCl 3 )δ9.11(d,J＝2.2Hz,1H),8.28-8.22(m,2H),7.96(m,2H),7.90-7.86(m,2H),7.79(m,1H),7.64-7.57(m,2H),7.57-7.51(m,2H),7.47(m,1H).
13 C NMR(101MHz,CDCl 3 )δ151.83,147.19,136.20,136.13,133.71,133.57,131.53,129.44,129.21,128.47,128.39,127.80,127.70,127.67,126.90,126.50,126.01,125.32,125.22.Preparation example 10
6-methylquinoline (28.6 mg,0.2 mmol), bis (1, 5-cyclooctadiene) nickel (5.5 mg,10 mol%) and 2mL of diethylene glycol dimethyl ether were weighed in a 10mL reaction tube equipped with a magnetic stirring bar in a glove box. The reaction tube was sealed with a polytetrafluoroethylene-lined screw cap and removed from the glove box, and n-heptyl magnesium bromide (0.6 ml,1.0m in tetrahydrofuran) was added dropwise to the reaction tube via syringe under nitrogen. The reaction was stirred at 30℃for 20 min. Iodobenzene (0.4 mmol) was then added to the reaction tube under nitrogen and the reaction stirred at 30 ℃ for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3X 3 mL), and the combined layers were dried over anhydrous sodium sulfate, followed by the addition of excess 1, 2-dichloro-4, 5-dicyanobenzoquinone (0.3 mmol,68.1 mg). Evaporating the solvent under vacuum, and performing column chromatography separation by using a solvent with a ratio of petroleum ether to ethyl acetate to obtain a target product 6-methyl-3-phenylquinoline, wherein the yield is 79 percent.
1 H NMR(400MHz,CDCl 3 )δ9.14(d,J＝2.1Hz,1H),8.23(d,J＝2.1Hz,1H),8.06(d,J＝8.6Hz,1H),7.77-7.70(m,2H),7.65(s,1H),7.60-7.51(m,3H),7.49-7.43(m,1H),2.58(s,3H).
13 C NMR(101MHz,CDCl 3 )δ148.96,145.89,138.00,136.86,133.76,132.59,131.68,129.10,128.79,128.02,127.97,127.36,126.76,21.61.
PREPARATION EXAMPLE 11
7, 8-benzoquinoline (36.0 mg,0.2 mmol), bis (1, 5-cyclooctadiene) nickel (5.5 mg,10 mol%) and 2mL of diethylene glycol dimethyl ether were weighed in a 10mL reaction tube equipped with a magnetic stirring bar in a glove box. The reaction tube was sealed with a polytetrafluoroethylene-lined screw cap and removed from the glove box, and n-heptyl magnesium bromide (0.6 ml,1.0m in tetrahydrofuran) was added dropwise to the reaction tube via syringe under nitrogen. The reaction was stirred at 30℃for 20 min. Iodobenzene (0.4 mmol) was then added to the reaction tube under nitrogen and the reaction stirred at 30 ℃ for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3X 3 mL), and the combined layers were dried over anhydrous sodium sulfate, followed by the addition of excess 1, 2-dichloro-4, 5-dicyanobenzoquinone (0.3 mmol,68.1 mg). Evaporating the solvent under vacuum, and performing column chromatography separation by using a solvent with a ratio of petroleum ether to ethyl acetate to obtain the target product 3-phenylbenzo [ h ] quinoline, wherein the yield is 64% as a white solid.
1 H NMR(400MHz,CDCl 3 )δ9.33-9.23(m,2H),8.32(d,J＝2.3Hz,1H),7.94-7.87(m,1H),7.84(d,J＝8.8Hz,1H),7.78-7.70(m,5H),7.54(m,2H),7.47-7.41(m,1H).
13 C NMR(101MHz,CDCl 3 )δ147.88,145.51,137.92,134.54,133.57,133.33,131.31,129.17,128.19,128.15,128.05,127.86,127.38,127.19,126.19,125.46,124.29.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present patent is to be determined by the appended claims.

Claims (8)

1. A method for synthesizing 3-aryl quinoline compounds by nickel catalysis is characterized in that the synthetic method of the 3-aryl quinoline compounds IV is as follows:
quinoline I, n-heptyl format reagent II and iodobenzene III are used as raw materials, and two-step electrophilic addition and reduction elimination reactions are carried out under the condition of nitrogen through nickel catalysis, so that the 3-aryl quinoline compound IV can be obtained.
2. The method for synthesizing the 3-aryl quinoline compound by nickel catalysis according to claim 1, wherein the method comprises the following steps:
the quinoline compound I has a structure shown in a formula 1:
wherein R is various aliphatic hydrocarbon groups and halogen atoms.
3. The method for synthesizing the 3-aryl quinoline compound by nickel catalysis according to claim 1, wherein the method comprises the following steps:
the n-heptyl format reagent II has a structure shown in a formula 2:
4. the method for synthesizing the 3-aryl quinoline compound by nickel catalysis according to claim 1, wherein the method comprises the following steps:
the iodobenzene III has a structure shown in a formula 3:
wherein R' is various aliphatic hydrocarbon groups and halogen atoms.
5. The method for synthesizing the 3-aryl quinoline compound by nickel catalysis according to claim 1, wherein the method comprises the following steps:
the 3-aryl quinoline compound IV has a structure shown in a formula 4:
wherein R and R' are various aliphatic hydrocarbon groups and halogen atoms.
6. The method for synthesizing the 3-aryl quinoline compound by nickel catalysis according to claim 1, wherein the method comprises the following steps:
the molar amount of the n-heptyl format reagent is 1.5 times that of quinoline;
the molar quantity of the iodobenzene is 1-2 times of that of the quinoline.
7. The method for synthesizing the 3-aryl quinoline compound by nickel catalysis according to claim 1, wherein the method comprises the following steps:
the solvent adopted in the reaction is diethylene glycol dimethyl ether.
8. The method for synthesizing 3-arylquinoline compounds according to claim 1, wherein the method is characterized in that:
the reaction conditions are as follows: the first step, under the nitrogen environment, the temperature is 30 ℃, and the reaction is carried out for 20min through nickel catalysis; and secondly, reacting for 3 hours at the temperature of 30 ℃ in a nitrogen atmosphere.
CN202310614019.4A 2023-05-29 2023-05-29 Method for synthesizing 3-aryl quinoline compound by nickel catalysis Pending CN116655529A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115028641A (en) * 2022-07-19 2022-09-09 湖南大学 Method for synthesizing 5, 8-bifunctional substituted imidazo [1,2-a ] pyrazine compound by cobalt catalysis

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115028641A (en) * 2022-07-19 2022-09-09 湖南大学 Method for synthesizing 5, 8-bifunctional substituted imidazo [1,2-a ] pyrazine compound by cobalt catalysis

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