CN108558750B - Process for synthesizing 3-nitroquinoline derivative by solvent-free method - Google Patents
Process for synthesizing 3-nitroquinoline derivative by solvent-free method Download PDFInfo
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- CN108558750B CN108558750B CN201810758186.5A CN201810758186A CN108558750B CN 108558750 B CN108558750 B CN 108558750B CN 201810758186 A CN201810758186 A CN 201810758186A CN 108558750 B CN108558750 B CN 108558750B
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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
- C07D215/16—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
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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
- C07D215/16—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to a method for synthesizing 3-nitroquinoline in a solvent-free system, which comprises the following steps: under the condition of no solvent, nitroolefin and aryl azide substituted by ortho aldehyde group undergo [3+2] cycloaddition reaction under the action of a copper salt catalyst, wherein the nitroolefin is alkyl, substituted alkyl, aryl or substituted aryl nitroolefin, and the aryl in the aryl azide substituted by the ortho aldehyde group is aryl or substituted aryl. The invention has the beneficial effects that: the 3-nitroquinoline compound is obtained with high yield by adopting aryl azide and nitroolefin substituted by ortho-position aldehyde group and taking copper salt as a catalyst under the condition of no solvent. The raw materials are simple and easy to obtain, the reaction byproducts are only nitrogen and water, the atom utilization rate is high, the solvent-free strategy greatly shortens the reaction time, reduces the byproducts generated by the 2-azidobenzaldehyde and the solvent, and is simple and convenient in post-treatment and environment-friendly.
Description
Technical Field
The invention relates to a method for synthesizing 3-nitroquinoline in a solvent-free system, belonging to the technical field of organic and pharmaceutical synthesis.
Technical Field
Quinoline is an important nitrogen-containing heterocyclic compound in organic synthesis. Wherein, the quinoline substituted by the nitrogen atom at the 3-position widely exists in natural products, such as the alkaloid of the hederagenin class, has good antimalarial and anticancer activities, and in addition, some compounds containing the skeleton also have the characteristics of anticancer, antimalarial, antiasthmatic, antidiabetic, antibacterial, antitumor and the like. The 3-nitroquinoline compound as a precursor of the compound has the characteristics of stable property and easy derivatization, is concerned about organic synthesis, and has great potential in drug synthesis.
However, to date, the synthesis methods of 3-nitroquinoline compounds are very few, and there are three main methods: (1) the method has the advantages that the quinoline ring is directly nitrified, the selectivity is low, several position isomers are generated, the quinoline ring is oxidized to form quinoline oxynitride, and therefore, the direct nitration mode is rarely used for synthesizing the 3-nitroquinoline compound. (2) 2-aminobenzaldehyde and alpha-nitroketone compounds are condensed in alcohol solvents to obtain 3-nitroquinoline, but the ketone compounds are complicated in preparation and have strong limitation on substrates. (3) In 2004, the group of Yaoqing hair subjects reported that o-aminobenzaldehyde and nitroolefin were refluxed using benzene as a solvent under DABCO as an organic base to give 3-nitro-1, 2-dihydroquinoline, which was subsequently oxidized under DDQ or silica gel to give 3-nitroquinoline. This method is widely used, but has three problems, namely, benzene with high toxicity is used as a solvent in the first cycloaddition, anthranilic aldehyde is very easy to polymerize and expensive, and actually, the yield is low, the reaction is carried out in two steps, and equivalent alkali and oxidant are used, so that the post-treatment is complicated.
Disclosure of Invention
In order to solve the defects of the prior art, the invention adopts cheap and easily obtained ortho-position aldehyde group substituted aryl azide as a raw material, obtains the 3-nitroquinoline compound with nitroolefin under the catalysis of copper salt, and greatly improves the reaction rate by a solvent-free strategy. The reaction by-products are only nitrogen and water, the post-treatment is simple, and the method is an environment-friendly synthesis method.
In order to achieve the purpose, the invention is realized by the following technical scheme: the process for synthesizing the 3-nitroquinoline derivative by a solvent-free method is characterized by comprising the following steps: under the condition of no solvent, nitroolefin and aryl azide substituted by ortho aldehyde group undergo [3+2] cycloaddition reaction under the action of a copper salt catalyst, wherein the nitroolefin is alkyl, substituted alkyl, aryl or substituted aryl nitroolefin, and the aryl in the aryl azide substituted by the ortho aldehyde group is aryl or substituted aryl.
The specific reaction formula is shown as formula I:
in the formula I, Ar is aryl or substituted aryl, alkyl or substituted alkyl, and R is halogen, methyl, methoxy, hydrogen or aryl.
According to the scheme, the copper salt catalyst is selected from CuI, CuCl, CuBr and Cu2O or Cu (OTf)2。
According to the scheme, the copper salt catalyst is CuI.
According to the scheme, the dosage of the copper salt catalyst is 0.01-0.2 times of the dosage of the nitroolefin according to the amount of the substance.
According to the scheme, the dosage of the copper salt catalyst is 0.01 time of that of the nitroolefin according to the amount of the substance.
According to the above scheme, the reaction is carried out at a temperature ranging from 80 to 130 ℃.
According to the scheme, the reaction is carried out at 110 ℃.
According to the scheme, the dosage of the aryl azide substituted by the ortho aldehyde group is 1 to 5 times of that of the nitroolefin according to the amount of the substance.
According to the scheme, the dosage of the aryl azide substituted by the ortho aldehyde group is 1.5 to 2 times of that of the nitroolefin according to the amount of the substance.
According to the scheme, the reaction time is 2-8 hours.
The specific reaction formula of the catalyst CuI at 110 ℃ is as follows:
the specific reaction steps are as follows: mixing nitroolefin, ortho-aldehyde group substituted aryl azide and CuI, reacting for 2-8 hours under heating condition by magnetic stirring, dissolving with ethyl acetate after the reaction is finished, washing an organic layer with saturated saline solution, drying anhydrous sodium sulfate, evaporating under reduced pressure to remove an extraction solvent to obtain a crude product, and separating and purifying by column chromatography to obtain the product 3-nitroquinoline compound.
The invention has the beneficial effects that: the 3-nitroquinoline compound is obtained with high yield by adopting aryl azide and nitroolefin substituted by ortho-position aldehyde group and taking copper salt as a catalyst under the condition of no solvent. The method has the advantages of simple and easily obtained raw materials, only nitrogen and water as reaction byproducts, high atom utilization rate, greatly shortened reaction time by a solvent-free strategy, reduced byproducts generated by 2-azidobenzaldehyde and a solvent, simple and convenient post-treatment, environmental friendliness and potential application value.
Drawings
In order to more clearly illustrate the technical solution of the embodiment of the present invention, the drawings of the embodiment are briefly introduced below.
FIG. 1 is the present inventionMethod for synthesizing 2-phenyl-3-nitroquinoline compound in invention example 11H NMR characterization spectrum;
FIG. 2 shows the synthesis of 2-phenyl-3-nitroquinoline compound according to example 1 of the present invention13C NMR characterization spectrum;
FIG. 3 is a scheme showing the synthesis of 2- (2-bromophenyl) -3-nitroquinoline compound of example 2 of the present invention1H NMR characterization spectrum;
FIG. 4 shows the synthesis of 2- (2-bromophenyl) -3-nitroquinoline compound of example 2 of the present invention13C NMR characterization spectrum;
FIG. 5 shows a scheme for synthesizing a 2-phenyl-3-nitro-7-fluoroquinoline compound according to example 3 of the present invention1H NMR characterization spectrum;
FIG. 6 shows a scheme for synthesizing a 2-phenyl-3-nitro-7-fluoroquinoline compound according to example 3 of the present invention13C NMR characterization spectrum;
FIG. 7 shows the synthesis of 2- (2-furyl) -3-nitroquinoline compound in example 4 of the present invention1H NMR characterization spectrum;
FIG. 8 shows the synthesis of 2- (2-furyl) -3-nitroquinoline according to example 4 of the present invention13C NMR characterization spectrum;
FIG. 9 shows a scheme for synthesizing a 2-phenyl-3-nitro-6, 7-dimethoxyquinoline compound according to example 5 of the present invention1H NMR characterization spectrum;
FIG. 10 shows a scheme for synthesizing a 2-phenyl-3-nitro-6, 7-dimethoxyquinoline compound according to example 5 of the present invention13C NMR characterization spectrum.
Detailed Description
In order to better understand the present invention, the following examples are further provided to illustrate the present invention, but the present invention is not limited to the following examples.
Example 1:
the method comprises the following specific steps: adding nitrostyrene (1mmol), 2-azidobenzaldehyde (1.5mmol) and CuI (0.01mmol) into a round-bottom flask (50mL), magnetically stirring at 110 ℃ for reaction for 2 hours, dissolving the mixture with ethyl acetate, washing an organic layer with saturated saline solution, drying the organic layer with anhydrous sodium sulfate, decompressing and steaming to remove an extraction solvent to obtain a crude product, and performing column separation and purification on the crude product by using ethyl acetate/petroleum ether (1: 10(V/V) as a leacheate to obtain a product 2-phenyl-3-nitroquinoline which is a yellow solid and has the yield of 90%.
As shown in fig. 1 and fig. 2, the nuclear magnetic hydrogen spectrum result of the obtained product is as follows:1H NMR(600MHz,DMSO-d6):8.60(s,1H),8.20(d,J＝8.4Hz,1H),7.90(d,J＝8.4Hz,1H),7.86(t,J＝7.8Hz,1H),7.63(t,J＝7.2Hz,1H),7.58(d,J＝7.8Hz,2H),7.30(d,J＝7.8Hz,2H),2.42(s,3H).13C NMR(100MHz,CDCl3,ppm)152.1,148.3,143.9,137.0,132.8,132.6,129.8,129.6,128.7,128.6,128.4,128.1,125.5.
example 2:
the method comprises the following specific steps: adding nitro o-bromostyrene (1mmol), 2-azidobenzaldehyde (2mmol) and CuI (0.01mmol) into a round-bottom flask (50mL), magnetically stirring at 110 ℃ for reaction for 3 hours, dissolving with ethyl acetate, washing an organic layer with saturated saline solution, drying with anhydrous sodium sulfate, decompressing and steaming to remove an extraction solvent to obtain a crude product, and performing column separation and purification on the crude product by using ethyl acetate/petroleum ether ═ 1:10(V/V) as a leacheate to obtain a product 2- (2-bromophenyl) -3-nitroquinoline which is a yellow solid with the yield of 88%.
As shown in fig. 3 and 4, the nuclear magnetic hydrogen spectrum results of the obtained product are as follows:1H NMR(600MHz,CDCl3,ppm)8.98(s,1H),8.25(d,J＝8.4Hz,1H),8.06(d,J＝7.8Hz,1H),7.95(t,J＝7.2Hz,1H),7.74(t,J＝7.2Hz,1H),7.65(d,J＝7.8Hz,1H),7.59-7.45(m,2H),7.34(t,J＝7.2Hz,1H).13C NMR(100MHz,CDCl3,ppm)152.2,148.5,143.0,139.4,133.4,133.3,132.4,130.3,130.1,129.8,129.0,128.9,127.7,126.0,121.8.
example 3:
the method comprises the following specific steps: to a round-bottomed flask (50mL) were added nitrostyrene (1mmol), 2-azido-4-fluorobenzaldehyde (1.5mmol), Cu2O (0.01mmol), reacting for 4 hours under magnetic stirring at 110 ℃, dissolving with ethyl acetate, washing the organic layer with saturated saline solution, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove the extraction solvent to obtain a crude product, and carrying out column separation and purification on the crude product by using ethyl acetate/petroleum ether (1: 15 (V/V)) as eluent to obtain the product 2-phenyl-3-nitro-7-fluoroquinoline, and producing the productThe product was a yellow solid with a yield of 85%.
As shown in fig. 5 and 6, the nuclear magnetic hydrogen spectrum results of the obtained product are as follows:1H NMR(600MHz,CDCl3,ppm)8.70(s,1H),8.03-7.97(m,1H),7.86(d,J＝9.6Hz,1H),7.65(s,2H),7.48-7.51(m,4H).13C NMR(150MHz,CDCl3,ppm)166.0,164.3,153.3,149.6(d,J＝13.4Hz),143.5,136.7,132.7,130.8(d,J＝10.4Hz),129.8,128.8,122.5,119.3(d,J＝25.9Hz),113.8(d,J＝21.0Hz).
example 4:
the method comprises the following specific steps: adding 2-nitrofuranstyrene (1mmol), 2-azidobenzaldehyde (1.5mmol) and CuCl (0.01mmol) into a round-bottom flask (50mL), magnetically stirring at 130 ℃ for reaction for 3 hours, dissolving with ethyl acetate, washing an organic layer with saturated saline solution, drying with anhydrous sodium sulfate, evaporating under reduced pressure to remove an extraction solvent to obtain a crude product, and carrying out column separation and purification on the crude product by using ethyl acetate/petroleum ether ═ 1:15(V/V) as a leacheate to obtain a product 2- (2-furyl) -3-nitroquinoline, wherein the product is a yellow solid, and the yield is 75%.
As shown in fig. 7 and 8, the nuclear magnetic hydrogen spectrum results of the obtained product are as follows:1H NMR(400MHz,CDCl3,ppm)8.45(s,1H),8.16(d,J＝8.4Hz,1H),7.83-7.89(m,2H),7.65-7.60(m,2H),7.23(d,J＝3.6Hz,1H),6.59-6.60(m,1H).13C NMR(100MHz,CDCl3,ppm)149.7,148.1,145.2,142.3,140.6,132.6,131.7,129.6,128.4,128.4,125.3,113.1,112.3.
example 5:
the method comprises the following specific steps: adding nitrostyrene (1mmol), 2-azido-4, 5-dimethoxybenzaldehyde (1.8mmol) and CuBr (0.01mmol) into a round-bottom flask (50mL), reacting at 100 ℃ under magnetic stirring for 4 hours, dissolving with ethyl acetate, washing an organic layer with saturated saline solution, drying with anhydrous sodium sulfate, evaporating under reduced pressure to remove an extraction solvent to obtain a crude product, and performing column separation and purification on the crude product by using ethyl acetate/petroleum ether (1: 2.5(V/V) as a leacheate to obtain the product 2-phenyl-3-nitro-6, 7-dimethoxyquinoline, wherein the product is a yellow solid, and the yield is 73%.
As shown in fig. 9 and 10, the nuclear magnetic hydrogen spectrum results of the obtained product are as follows:1H NMR(600MHz,CDCl3,ppm)8.55(s,1H),7.60(d,J＝4.8Hz,2H),7.52-7.44(m,4H),7.15(s,1H),4.05(s,3H),4.04(s,3H).13C NMR(100MHz,CDCl3,ppm)155.3,151.4,150.3,146.1,142.5,137.6,130.9,129.1,128.6,128.0,121.4,108.1,105.2,56.5,56.3.
the method adopts cheap and easily available CuI as a catalyst to catalyze the reaction of nitroolefin and 2-azidobenzaldehyde, and uses a solvent-free strategy to greatly accelerate the reaction and efficiently synthesize the 3-nitro-substituted quinoline compound.
The above embodiments do not limit the present invention in any way, and all technical solutions obtained by means of equivalent substitution or equivalent minor changes fall within the scope of the present invention.
Claims (9)
1. The process for synthesizing the 3-nitroquinoline derivative by a solvent-free method is characterized by comprising the following steps: under the condition of no solvent, nitroolefin 1 and ortho aldehyde group substituted aryl azide 2 undergo [4+2] cycloaddition reaction under the action of a copper salt catalyst, wherein the copper salt catalyst is selected from CuI, CuCl or CuBr, and the specific reaction formula is shown as formula I:
in the formula I, Ar is aryl or substituted aryl, alkyl or substituted alkyl, and R is halogen, methyl, methoxy, hydrogen or aryl.
2. The process according to claim 1, characterized in that: the copper salt catalyst is CuI.
3. The process according to any one of claims 1 to 2, characterized in that: the dosage of the copper salt catalyst is 0.01 to 0.2 times of the dosage of the nitroolefin according to the amount of the substance.
4. The process according to claim 3, characterized in that: the dosage of the copper salt catalyst is 0.01 time of that of the nitroolefin according to the amount of the substance.
5. The process according to claim 1, characterized in that: the reaction is carried out at a temperature in the range of 80 to 130 ℃.
6. The process according to claim 5, characterized in that: the reaction was carried out at 110 ℃.
7. The process according to claim 1, characterized in that: the dosage of the ortho-aldehyde group substituted aryl azide 2 is 1 to 5 times of the dosage of the nitroolefin 1 according to the amount of substances.
8. The process according to claim 7, characterized in that: the dosage of the ortho-aldehyde group substituted aryl azide 2 is 1.5 to 2 times of the dosage of the nitroolefin 1 according to the amount of substances.
9. The process according to claim 1, characterized in that: the reaction time is 2-8 hours.
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