CN106380463B - Method for synthesizing quinoline derivative - Google Patents
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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- 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
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Abstract
The invention provides a method for synthesizing quinoline derivatives, which comprises the following steps of: 1: 1.2-2 sequentially adding aromatic amine, electron-withdrawing alkyne and ketone, adding a solvent according to the proportion that 1mmol of aromatic amine is added into 2-4 mL, and then adding a catalyst Cu (OTf)2The preparation method comprises the following steps of (copper trifluoromethanesulfonate) and an additive HOTf (trifluoromethanesulfonic acid), wherein the addition amounts of the copper trifluoromethanesulfonate and the additive HOTf are respectively 0.8-5% and 1.8-10% of the molar amount of the aromatic amine, reacting for 10-24 h under an oil bath condition at 100-120 ℃, cooling to room temperature, adding water, extracting for three times by using ethyl acetate, combining organic layers, concentrating under reduced pressure, and purifying a product by column chromatography to obtain the quinoline derivative. The method has the characteristics of cheap reaction substrates, high yield, good selectivity, easy separation and purification, less pollution and simple steps.
Description
Technical Field
The invention relates to a quinoline derivative, in particular to a method for synthesizing the quinoline derivative.
Background
Quinoline and derivatives thereof are important organic heterocyclic compounds, widely exist in nature, and are widely applied to the fields of drug screening, chemical analysis, dye industry and the like. There are many methods for synthesizing quinoline derivatives, mainly: Skraup-Doebner-Miller synthesis, Friedlander-Pfitizge-Combes synthesis, Bischler-Napieralski synthesis (tetrahedron. Lett, 2000, 41, 531, 533; org. Lett, 2004, 6, 3965-. The synthesis method of quinoline compounds has been the focus of research (see: g.r.hummphrey, j.t.kuethe, Chem, Rev,2006,106,2875), and the most representative method for industrially synthesizing quinoline at present is Skraup synthesis, which uses arylamine, concentrated sulfuric acid, glycerol and mild oxidant to heat together to prepare quinoline derivatives. In the reaction process, glycerin is dehydrated into acrolein under the action of concentrated sulfuric acid at high temperature, then condensed with aniline into dihydroquinoline, and finally oxidized to obtain quinoline, nitrobenzene or arsenic acid is commonly used as a catalyst method, but the reaction is carried out in concentrated sulfuric acid at high temperature. Combes synthesis from aromatic amines and beta-bisKetones condense to quinoline rings in an acidic environment. The method is characterized in that arylamine and 1, 3-dicarbonyl compound are condensed to obtain beta-amino-ketene, and the beta-amino-ketene is cyclized under the action of concentrated sulfuric acid to obtain the quinoline derivative. However, when an electron-withdrawing group is present on the aromatic amine ring, the electron cloud density on the benzene ring is lowered, and the electrophilic substitution reaction is not facilitated. When the 1, 3-dicarbonyl compound (R)1-CO-CH2CO-R2) R in (1)1And R2When the two isomers are different, the condensation reaction in the first step has two possibilities, two beta-amino-ketenes are generated, and the cyclization product is a mixture containing two isomers.
In the beginning of the last eighties, methods for preparing quinolines by first coupling a transition metal-catalyzed terminal alkyne compound with an ortho-position aniline having a halogen, followed by cyclization, were reported (see (a) Muller, T.E.; Beller, M.Chem.Rev.1998,98,675; b) Roundhill, D.M.Chem.Rev.1992,92,1.(c) Bryndza, H.E.; Tam, W.Chem.Rev.1988,88,1163), which are important methods for synthesizing quinoline derivatives (see (a) Hartung, C.G.; Brendl, C.; Tillack, A.; Beller, M.Tetrahedron 2000,56, 5157; Kawatsura, M.; Hartwwig, J.J.Chem.Am.Trans.122, J.T.95J.C.; Esang E.22, Esang J.C.1999; Breund, Esang J.22, Esang J.E.22, Esang J.22, Esang J.52, Esang J.E., organomet, chem.1998,566,277), has been successfully applied to the synthesis of natural products and biomimetic drugs (see: z.z.shi, c.zhang, s.li, d.l.pan, s.t.ding, y.x.cui, n.jiao, angelw.chem.int.ed.2009, 48,4572).
Chinese patent CN104151235A discloses a preparation method of quinoline derivatives, which is to synthesize the quinoline derivatives by aniline and ketene or olefine aldehyde derivatives with silver trifluoromethanesulfonate as a catalytic substituent. However, this patent still has some disadvantages: quinoline derivatives having electron-withdrawing ester groups at the 2,4 positions could not be prepared.
The current synthetic methods have many disadvantages: mainly has harsh reaction conditions, high reaction temperature, high temperature and high pressure, difficult separation and strong restriction of reaction substrates, so the method for synthesizing the quinoline derivatives of the substituent groups is very limited. In addition, in the process of utilizing metal catalysis, the activity of the catalyst is limited, and the defects cause that the operation difficulty of the preparation process is increased, the health of operators is harmed, and the environmental pollution is serious. The existing methods for synthesizing quinoline derivatives are also ubiquitous: needs active reaction substrates, has low reaction rate, long reaction time, more byproducts and difficult treatment, and has too single reaction form (resulting in great limitation of the synthesized product). In view of this, it is important to develop a novel preparation method of quinoline derivatives.
Disclosure of Invention
Aiming at the defects of the existing quinoline derivative synthesis, the invention aims to provide a method for synthesizing the quinoline derivative, which has the advantages of simple operation, high yield, easy separation and purification of products and less pollution.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows: a method of synthesizing a quinoline derivative, comprising the method steps of:
in a reaction vessel, the molar ratio of 1: 1: 1.2-2 sequentially adding aromatic amine I, electron-withdrawing alkyne II and ketone III, adding a solvent according to the proportion that 1mmol of aromatic amine is added into 2-4 mL, and then adding a catalyst Cu (OTf)2Copper trifluoromethanesulfonate and an additive HOTf (trifluoromethanesulfonic acid), wherein the addition amounts of the copper trifluoromethanesulfonate and the additive HOTf are respectively 0.8-5% and 1.8-10% of the molar amount of the aromatic amine, the mixture reacts for 10-24 h under the condition of an oil bath at 100-120 ℃, the mixture is cooled to room temperature, water is added, ethyl acetate is used for extraction for three times, organic layers are combined, the mixture is concentrated under reduced pressure, and a product is purified by column chromatography to obtain a quinoline derivative product, wherein the reaction general formula of the synthetic method is as follows:
the chemical structural general formula of the quinoline derivative synthesized by the method is as follows:
wherein R is1Is H, C1～C6Chain alkyl, C1～C6Chain alkoxy group, NO2OH, F, Cl or Br; r2Is H, a formate group, C1～C6A chain alkyl group or a phenyl group; r3Is pyridyl, C3～C6Alkyl, cycloalkyl, thienyl, aryl.
The aromatic amine I is aniline, o-fluoroaniline, m-fluoroaniline, p-fluoroaniline, o-chloroaniline, m-chloroaniline, p-chloroaniline, o-bromoaniline, m-bromoaniline, p-bromoaniline, o-nitroaniline, m-nitroaniline, p-nitroaniline, o-methoxyaniline, m-methoxyaniline, p-methoxyaniline, o-methylaniline, m-methylaniline, p-methylaniline, o-trifluoroaniline, m-trifluoroaniline or p-trifluoroaniline.
The electron-withdrawing alkyne II is dimethyl butynedioate, diethyl butynedioate, methyl phenylpropargyl acid, ethyl phenylpropargyl acid, methyl propiolate, methyl butynoate, ethyl propiolate or ethyl butynoate.
The ketone III is 2-acetylpyridine, o-fluoro acetophenone, m-fluoro acetophenone, p-fluoro acetophenone, o-chloro acetophenone, m-chloro acetophenone, p-chloro acetophenone, o-bromo acetophenone, m-bromo acetophenone, p-bromo acetophenone, o-methoxy acetophenone, m-methoxy acetophenone, p-methoxy acetophenone, o-methyl acetophenone, m-methyl acetophenone, p-methyl acetophenone, o-trifluoro acetophenone, m-fluoro acetophenone, p-trifluoro acetophenone, 1-pentanone, 1-hexanone, 1-heptanone, 2-acetyl thiophene or 2-acetyl pyrrole.
The solvent is toluene, hexanitrile or THF.
The column chromatography conditions are as follows: a 300-400 mesh silica gel column, wherein the eluent is a mixture of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 2-1: 10.
The method for synthesizing the quinoline derivative designed by the technical scheme has the beneficial effects that:
1. the invention has less acid consumption and reduces the environmental pollution;
2. the method has simple reaction substrate and wide source, is suitable for aniline substituted by various functional groups (including aniline substituted by functional groups with large steric hindrance at the ortho position), and has small influence of the stereo effect on the reaction;
3. some of the products of the invention, such as: the IV site of the reaction general formula is a pyridine substituent group, and a main core of the functional material can be prepared;
4. the method has the advantages of cheap reaction substrate, high yield, good selectivity, easy separation and purification, less pollution and simple steps, can omit the steps of protecting and deprotecting the functional group and can be widely applied to the aspects of ligands, pharmaceutical intermediates and photoelectric materials of organic chemical reactions.
Drawings
FIG. 1 shows the preparation of the compound 4- (pyridin-2-yl) quinoline-2-carboxylic acid methyl ester1H NMR profile;
FIG. 2 shows the preparation of the compound 4- (pyridin-2-yl) quinoline-2-carboxylic acid methyl ester13C NMR characterization chart.
Detailed Description
The following examples are provided to illustrate the method of synthesizing quinoline derivatives according to the present invention.
Example 1
A method for synthesizing 4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester comprises the following steps:
1.0mmol (93mg) of aniline, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (145.2mg) of 2-acetylpyridine, and the catalyst Cu (OTf)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), 2mL of acetonitrile solvent, reacting in 100 deg.C oil bath for 10h, cooling to room temperature, adding 5mL of water, extracting with ethyl acetate for three times, combining organic layers, concentrating under reduced pressure, purifying by column chromatography, 300. degreeCSilica gel column of 400 mesh, eluent mixture of ethyl acetate and petroleum ether in a volume ratio of 1:5, to obtain 240.3mg of white solid product with 91% yield and 99.9% purity.1H NMR(400MHz,CDCl3)ppm:8.86(d,J＝4.8Hz,1H),8.39(d,J＝8.4Hz,1H),8.33(s,1H),8.24(d,J＝8.4Hz,1H),7.91-7.95(td,1H),7.80-7.84(m,1H),7.64-7.71(m,2H),7.44-7.47(m,1H),4.11(s,3H)；13C NMR(100MHz,CDCl3)ppm:165.8,156.1,149.8,148.4,147.5,137.0,131.0,130.2,129.1,127.1,125.6,124.9,123.4,121.3,53.2；HRMS(EI)Calcd.for C16H12N2O2:[M+],264.0899.Found:m/z 264.0897.
Wherein the chemical structural general formula of the 4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester is
Example 2
A method for synthesizing 6-methyl-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester comprises the following steps:
to the reaction vessel were added, in order, p-methylaniline 1.0mmol (107mg), dimethyl butynedioate 1.0mmol (142.1mg), 2-acetylpyridine 1.2mmol (145.2mg), catalyst Cu (OTf)20.005mmol (1.8mg), 0.01mmol (1.5mg) of HOTf and 2mL of acetonitrile as a solvent are reacted in an oil bath at 100 ℃ for 10 hours, the reaction solution is cooled to room temperature, 5mL of water is added, extraction is carried out three times by using ethyl acetate, organic layers are combined, reduced pressure concentration is carried out, the product is purified by column chromatography, a 300-mesh 400-mesh silica gel column and an eluent are a mixture of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1:5, 267.0mg of a white solid product is obtained, the yield is 96 percent, and the purity is 99.9 percent.1H NMR(400MHz,CDCl3)ppm:8.85(d,J＝4.0Hz,1H),8.28(d,J＝9.6Hz,1H),8.27(s,1H),7.90-7.95(m,2H),7.63-7.68(m,2H),7.43-7.46(m,1H),4.09(s,3H),2.53(s,3H)；13C NMR(100MHz,CDCl3)ppm:165.9,156.4,149.8,146.6,146.5,139.6,137.0,132.6,132.4,130.8,127.2,124.9,124.3,123.3,121.5,53.1,22.1；HRMS(EI)Calcd.for C17H14N2O2:[M+],278.1055.Found:m/z 278.1057.
Wherein the chemical structure general formula of the methyl 6-methyl-4- (pyridine-2-yl) quinoline-2-carboxylate is as follows:
example 3
A synthetic method of 6-methoxy-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester comprises the following steps:
into the reaction vessel were successively charged 1.0mmol (123.1mg) of p-anisidine, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (145.2mg) of 2-acetylpyridine, and the catalyst Cu (OTf)20.005mmol (1.8mg), 0.01mmol (1.5mg) of HOTf, 2mL of acetonitrile solvent, reacting in an oil bath at 100 ℃ for 10h, cooling to room temperature, adding 5mL of water, extracting three times with ethyl acetate, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-400-mesh silica gel column, and using a mixture of ethyl acetate and petroleum ether as an eluent in a volume ratio of 1:5 to obtain 273.5mg of a white solid product with the yield of 93 percent and the purity of 99.9 percent.1H NMR(400MHz,CDCl3)ppm:8.85(d,J＝4.0Hz,1H),8.26-8.28(m,2H),7.91-7.94(t,1H),7.70(d,J＝8.0Hz,1H),7.57(s,1H),7.43-7.47(m,2H),4.08(s,3H),3.86(s,3H)；13C NMR(100MHz,CDCl3)ppm:165.9,159.9,156.6,149.7,145.4,144.9,144.6,137.1,132.5,128.5,124.7,123.3,123.0,121.9,103.3,55.4,53.0；HRMS(EI)Calcd.for C17H14N2O3:[M+],294.1004.Found:m/z 294.1007.
Wherein the chemical structure of the 6-methoxy-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester
Has the general formula
Example 4
A synthetic method of 6-fluoro-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester comprises the following steps:
into the reaction vessel were charged p-fluoroaniline 1.0mmol (111mg), dimethyl butynedioate 1.0mmol (142.1mg), 2-acetylpyridine 1.2mmol (145.2mg), catalyst Cu (OTf)20.005mmol (1.8mg), 0.01mmol (1.5mg) of HOTf, 2mL of acetonitrile solvent, reaction in an oil bath at 120 ℃ for 24h, cooling to room temperature, adding 5mL of water, extracting three times with ethyl acetate, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-mesh 400-mesh silica gel column, and using a mixture of ethyl acetate and petroleum ether as an eluent in a volume ratio of 1:2 to obtain 234.1mg of a white solid product with the yield of 83% and the purity of 99.9%.1H NMR(400MHz,CDCl3)ppm:8.86(d,J＝4.8Hz,1H),8.37-8.41(m,1H),8.34(s,1H),7.92-7.97(m,2H),7.70(d,J＝7.6Hz,1H),7.57-7.61(m,1H),7.45-7.48(m,2H),4.10(s,3H)；13C NMR(100MHz,CDCl3)ppm:165.6,160.9,155.8,149.9,146.9(d,J＝2.9Hz),146.7(d,J＝6.0Hz),145.6,137.2,133.7(d,J＝9.4Hz),128.2(d,J＝10.5Hz),124.7,123.6,121.9,120.7(d,J＝26.1Hz),109.4(d,J＝23.8Hz),53.2；HRMS(EI)Calcd.for C16H11FN2O2:[M+],282.0805.Found:m/z282.0807.
Wherein the chemical structure of the 6-fluoro-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester is shown in the specification
The formula is as follows:
example 5
A method for synthesizing 6-chloro-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester comprises the following steps:
into a reaction vessel were successively charged 1.0mmol (127mg) of p-chloroaniline, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, and the catalyst Cu (OTf)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), 2mL of acetonitrile solvent, reacting in an oil bath at 120 ℃ for 12h, cooling to room temperature, adding 5mL of water, extracting with ethyl acetate three times, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-mesh 400-mesh silica gel column, and using a mixture of ethyl acetate and petroleum ether as an eluent in a volume ratio of 1:3 to obtain 241.4mg of a white solid productThe yield is 82%, and the purity is 99.9%. ppm:8.87(d, J ═ 4.0Hz,1H),8.28-8.33(m,3H),7.92-7.96(t,1H),7.75(d, J ═ 9.2Hz,1H),7.69(d, J ═ 8.0Hz,1H),7.46-7.49(m,1H),4.10(s, 3H);13C NMR(100MHz,CDCl3)ppm:165.5,155.6,149.9,147.6,146.8,146.5,137.2,135.4,132.5,131.3,127.7,124.79,124.76,123.6,122.1,53.3；HRMS(ESI-TOF)m/z calcd for C16H11ClN2O2[M+H]+298.0629,found 298.0577.
wherein the chemical structure of the 6-chloro-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester is shown in the specification
The formula is as follows:
example 6
A synthetic method of 6-bromo-4- (pyridin-2-yl) quinoline-2-carboxylic acid methyl ester comprises the following steps:
to a reaction vessel were added, in order, p-bromoaniline 1.0mmol (171mg), butynedioic acid dimethyl ester 1.0mmol (142.1mg), phenylacetylene 1.2mmol (122.4mg), catalyst Cu (OTf)20.005mmol (1.8mg), 0.01mmol (1.5mg) of HOTf, 2mL of acetonitrile solvent, reaction in an oil bath at 120 ℃ for 12h, cooling to room temperature, adding 5mL of water, extracting three times with ethyl acetate, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-400-mesh silica gel column, and using a mixture of ethyl acetate and petroleum ether as an eluent in a volume ratio of 1:3 to obtain 287.3mg of a white solid product with the yield of 84% and the purity of 99.9%.1H NMR(400MHz,CDCl3)ppm:8.86(d,J＝4.0Hz,1H),8.45(s,1H),8.32(s,1H),8.24(d,J＝9.2Hz,1H),7.92-7.96(t,1H),7.88(d,J＝9.2Hz,1H),7.69(d,J＝7.6Hz,1H),7.46-7.49(t,1H),4.11(s,3H)；13C NMR(100MHz,CDCl3)ppm:165.5,155.6,150.0,147.8,147.0,146.5,137.3,133.9,132.6,128.2,128.1,124.8,123.9,123.7,122.1,53.3；HRMS(EI)Calcd.for C16H11BrN2O2:[M+],342.0004.Found:m/z 342.0010.
Wherein the chemical structure general formula of the methyl 6-bromo-4- (pyridin-2-yl) quinoline-2-carboxylate is as follows:
example 7
A method for synthesizing 7-methyl-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester comprises the following steps:
to a reaction vessel were added, in order, m-methylaniline 1.0mmol (107mg), dimethyl butynedioate 1.0mmol (142.1mg), phenylacetylene 1.2mmol (122.4mg), catalyst Cu (OTf)20.005mmol (1.8mg), 0.01mmol (1.5mg) of HOTf, 2mL of acetonitrile solvent, reaction in an oil bath at 120 ℃ for 12h, cooling to room temperature, adding 5mL of water, extracting three times with ethyl acetate, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-mesh 400-mesh silica gel column, and using a mixture of ethyl acetate and petroleum ether as an eluent in a volume ratio of 1:5 to obtain 253.1mg of a white solid product, wherein the yield is 91 percent, and the purity is 99.9 percent.1H NMR(400MHz,CDCl3)ppm:8.81(d,J＝2.8Hz,1H),8.25(s,1H),8.15(s,1H),8.10(d,J＝8.4Hz,1H),7.85-7.88(t,1H),7.65(d,J＝7.6Hz,1H),7.46(d,J＝8.4Hz,1H),7.39-7.41(t,1H),4.08(s,3H),2.56(s,3H)；13C NMR(100MHz,CDCl3)ppm:165.8,156.2,149.8,148.6,147.3,147.1,140.5,136.9,131.4,129.9,125.19,125.14,124.8,123.3,120.6,53.0,21.6；HRMS(EI)Calcd.for C17H14N2O2:[M+],278.1055.Found:m/z 278.1058.
Wherein the chemical structure general formula of the 7-methyl-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester is as follows:
example 8
A method for synthesizing 7-methoxy-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester comprises the following steps:
to the reaction vessel were added, in order, m-methoxyaniline 1.0mmol (123.1mg), butynedioic acid dimethyl ester 1.0mmol (142.1mg), and phenylacetylene 1.2mmol (122.4mg)) Catalyst Cu (OTf)20.005mmol (1.8mg), 0.01mmol (1.5mg) of HOTf, 2mL of nitrile solvent, reacting in an oil bath at 120 ℃ for 12h, cooling to room temperature, adding 5mL of water, extracting with ethyl acetate three times, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-mesh 400-mesh silica gel column, and using a mixture of ethyl acetate and petroleum ether as an eluent in a volume ratio of 1:5 to obtain 267.6mg of a white solid product with the yield of 91 percent and the purity of 99.9 percent.1H NMR(400MHz,CDCl3)ppm:8.84(d,J＝4.4Hz,1H),8.20(s,1H),8.13(d,J＝9.2Hz,1H),7.89-7.93(t,1H),7.69(s,1H),7.68(d,J＝8.0Hz,1H),7.42-7.45(t,1H),7.30(d,J＝9.2Hz,1H),4.10(s,3H),3.98(s,3H)；13C NMR(100MHz,CDCl3)ppm:166.0,161.1,156.4,150.5,149.8,147.7,147.2,137.0,126.7,124.9,123.4,122.6,122.5,119.6,108.5,55.7,53.2；HRMS(EI)Calcd.for C17H14N2O3:[M+],294.1004.Found:m/z 294.1007.
Wherein the chemical structure general formula of the 7-methoxy-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester is as follows:
example 9
A method for synthesizing 8-methyl-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester comprises the following steps:
1.0mmol (1107mg) of o-methylbenzylamine, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, and a catalyst Cu (OTf) were sequentially charged into a reaction vessel20.005mmol (1.8mg), 0.01mmol (1.5mg) of HOTf, 2mL of acetonitrile solvent, reaction in an oil bath at 120 ℃ for 12h, cooling to room temperature, adding 5mL of water, extracting three times with ethyl acetate, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-mesh 400-mesh silica gel column, and using a mixture of ethyl acetate and petroleum ether as an eluent in a volume ratio of 1:5 to obtain 230.8mg of a white solid product with the yield of 83% and the purity of 99.9%.1H NMR(400MHz,CDCl3)ppm:8.84(d,J＝4.4Hz,1H),8.28(s,1H),8.00(d,J＝8.4Hz,1H),7.88-7.92(t,1H),7.66(d,J＝7.2Hz,2H),7.51-7.55(t,1H),7.42-7.45(t,1H),4.07(s,3H),2.95(s,3H)；13C NMR(100MHz,CDCl3)ppm:166.1,156.3,149.8,147.6,147.5,146.3,139.1,136.8,130.3,128.8,127.2,125.0,123.4,123.2,121.2,52.9,18.3；HRMS(EI)Calcd.for C17H14N2O2:[M+],278.1055.Found:m/z 278.1059.
Wherein the chemical structure general formula of the 8-methyl-4- (pyridine-2-yl) quinoline-2-carboxylic acid methyl ester is as follows:
example 10
A synthetic method of 7-methoxy-2, 4-diphenyl quinoline comprises the following steps:
in a reaction vessel were successively charged m-methoxyaniline 1.0mmol (123.1mg), phenylpropanoic acid methyl ester 1.0mmol (160.2mg), phenylacetylene 1.2mmol (122.4mg), catalyst Cu (OTf)20.005mmol (1.8mg), 0.01mmol (1.5mg) of HOTf and 2mL of acetonitrile as a solvent are reacted in an oil bath at 100 ℃ for 8 hours, the reaction solution is cooled to room temperature, 5mL of water is added, extraction is carried out three times by using ethyl acetate, organic layers are combined, reduced pressure concentration is carried out, the product is purified by column chromatography, a 300-mesh 400-mesh silica gel column and an eluent are a mixture of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1:5, 296.4mg of a white solid product is obtained, the yield is 95%, and the purity is 99.9%.1H NMR(400MHz,CDCl3)1H NMR(400MHz,CDCl3)ppm:8.16(d,J＝7.6Hz,2H),7.79(d,J＝6.8Hz,1H),7.68(s,1H),7.60(s,1H),7.46-7.56(m,8H),7.13(d,J＝9.2Hz,1H),4.00(s,3H)；13C NMR(100MHz,CDCl3)ppm:160.8,157.3,150.6,149.2,139.8,138.6,129.5,129.3,128.8,128.6,128.4,127.6,126.8,120.9,119.5,117.5,107.9,55.6；HRMS(ESI-TOF)m/z calcd for C22H18NO[M+H]+312.0383,found 312.0383.
Wherein, the chemical structural general formula of the 7-methoxy-2, 4-diphenyl quinoline is as follows:
example 11
A synthetic method of 7-trifluoromethyl-2, 4-diphenylquinoline comprises the following steps:
in a reaction vessel, m-trifluoromethylaniline 1.0mmol (161.1mg), phenylpropanoic acid methyl ester 1.0mmol (160.2mg), phenylacetylene 1.2mmol (122.4mg), catalyst Cu (OTf)20.005mmol (1.8mg), 0.01mmol (1.5mg) of HOTf, 2mL of acetonitrile solvent, reaction in an oil bath at 120 ℃ for 24h, cooling to room temperature, adding 5mL of water, extracting three times with ethyl acetate, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-400-mesh silica gel column, and using a mixture of ethyl acetate and petroleum ether as an eluent in a volume ratio of 1:5 to obtain 287.1mg of a white solid product with the yield of 82% and the purity of 99.9%.1H NMR(400MHz,CDCl3)ppm:8.54(s,1H),8.18(d,J＝7.6Hz,2H),7.99(d,J＝8.8Hz,1H),7.89(s,1H),7.60(d,J＝8.8Hz,1H),7.46-7.59(m,8H)；13C NMR(100MHz,CDCl3)ppm:158.2,149.3,147.9,138.9,137.7,131.3(q,J＝64.9),129.9,129.5,129.0,128.9,127.9(q,J＝8.6),127.6,127.4,127.0,125.5,122.8,121.8(q,J＝5.8),120.9；HRMS(ESI-TOF)m/z calcd for C22H15F3N[M+H]+350.1151,found 350.1159.
Wherein, the chemical structural general formula of the 7-trifluoromethyl-2, 4-diphenylquinoline is as follows:
example 12
A synthetic method of 2-methyl-6-methoxy-4-phenylquinoline comprises the following steps:
into the reaction vessel were charged p-anisidine 1.0mmol (123.1mg), methyl butynoate 1.0mmol (98.1mg), phenylacetylene 1.2mmol (122.4mg), catalyst Cu (OTf)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), 2mL of acetonitrile as solvent, reacted in 100 deg.C oil bath for 8h, cooled to room temperature, added with 5mL of water, extracted three times with ethyl acetate, combined organic layers, concentrated under reduced pressureAnd (3) purifying the product by column chromatography, wherein the product is subjected to 300-400-mesh silica gel column, and the eluent is a mixture of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1:10, so that 182.6mg of a white solid product is obtained, the yield is 73%, and the purity is 99.9%.1H NMR(400MHz,CDCl3)ppm:8.07-8.12(m,3H),7.68(s,1H),7.48-7.52(t,2H),7.36-7.44(m,2H),7.19(d,J＝2.4Hz,1H),3.96(s,3H),2.71(s,3H)；13C NMR(100MHz,CDCl3)ppm:157.6,154.8,144.1,143.3,140.0,131.8,128.84,128.76,128.11,127.3,121.5,120.0,101.9,55.6,19.2；HRMS(ESI-TOF)m/z calcd for C17H16NO[M+H]+250.1226,found 250.1229.
Wherein, the chemical structural general formula of the 2-methyl-6-methoxy-4-phenylquinoline is as follows:
example 13
A synthetic method of 7,8,9, 10-tetrahydrophenanthridine-6-carboxylic acid methyl ester comprises the following steps:
1.0mmol (93mg) of aniline, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.5mmol (147.2mg) of cyclohexanone, and the catalyst Cu (OTf)20.005mmol (1.8mg), 0.01mmol (1.5mg) of HOTf, 2mL of acetonitrile solvent, reaction in an oil bath at 120 ℃ for 12h, cooling to room temperature, adding 5mL of water, extracting three times with ethyl acetate, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-400-mesh silica gel column, and using a mixture of ethyl acetate and petroleum ether as an eluent in a volume ratio of 1:10 to obtain 226.6mg of a white solid product with the yield of 94% and the purity of 99.9%.1H NMR(400MHz,CDCl3)ppm:8.15(d,J＝8.4Hz,1H),7.96(d,J＝8.0Hz,1H),7.66-7.70(t,1H),7.58-7.62(t,1H),4.10(s,3H),3.18-3.19(t,2H),3.04-3.07(t,2H),1.95-1.98(m,2H),1.85-1.90(m,2H)；13C NMR(100MHz,CDCl3)ppm:167.4,150.4,144.8,143.5,130.4,128.7,128.2,128.1,127.7,127.4,52.7,26.5,25.6,22.1,21.8；HRMS(EI)Calcd.for C15H15NO2:[M+],241.1103.Found:m/z 241.1108.
Wherein, the chemical structural general formula of the 7,8,9, 10-tetrahydrophenanthridine-6-carboxylic acid methyl ester is as follows:
example 14
A synthetic method of 2-methyl-7, 8,9, 10-tetrahydrophenanthridine-6-carboxylic acid methyl ester comprises the following steps:
into the reaction vessel were charged, in order, p-methylaniline 1.0mmol (107mg), butynedioic acid dimethyl ester 1.0mmol (142.1mg), cyclohexanone 1.5mmol (147.2mg), catalyst Cu (OTf)20.005mmol (1.8mg), 0.01mmol (1.5mg) of HOTf, 2mL of acetonitrile solvent, reaction in an oil bath at 120 ℃ for 12h, cooling to room temperature, adding 5mL of water, extracting three times with ethyl acetate, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-mesh 400-mesh silica gel column, and using a mixture of ethyl acetate and petroleum ether as an eluent in a volume ratio of 1:5 to obtain 247.4mg of a white solid product with the yield of 97% and the purity of 99.9%.1H NMR(400MHz,CDCl3)ppm:8.03(d,J＝8.4Hz,1H),7.70(s,1H),7.50(d,J＝8.4Hz,1H),4.02(s,3H),3.12-3.15(t,2H),3.03-3.06(t,2H),2.55(s,3H),1.92-1.98(m,2H),1.83-1.88(m,2H)；13C NMR(100MHz,CDCl3)ppm:167.5149.3,143.4,142.8,137.9,131.0,130.2,128.5,128.2,121.5,52.7,26.6,25.8,22.3,22.1,21.9；HRMS(EI)Calcd.for C16H17NO2:[M+],255.1259.Found:m/z 255.1257.
Wherein the chemical structural general formula of the 2-methyl-7, 8,9, 10-tetrahydrophenanthridine-6-carboxylic acid methyl ester is as follows:
example 15
A synthetic method of 2-trifluoromethyl-7, 8,9, 10-tetrahydrophenanthridine-6-carboxylic acid methyl ester comprises the following steps:
sequentially adding p-trifluoromethylaniline into a reaction vessel1.0mmol (161mg), dimethyl butynedioate 1.0mmol (142.1mg), cyclohexanone 1.5mmol (147.2mg), catalyst Cu (OTf)20.005mmol (1.8mg), 0.01mmol (1.5mg) of HOTf, 2mL of acetonitrile solvent, reaction in an oil bath at 120 ℃ for 12h, cooling to room temperature, adding 5mL of water, extracting three times with ethyl acetate, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-mesh 400-mesh silica gel column, and using a mixture of ethyl acetate and petroleum ether as an eluent in a volume ratio of 1:10 to obtain 268.9mg of a white solid product with the yield of 87% and the purity of 99.9%.1H NMR(400MHz,CDCl3)ppm:8.26-8.28(m,2H),7.84-7.87(dd,J＝8.8,1.6Hz,1H),4.05(s,3H),3.21-3.24(t,2H),3.04-3.07(t,2H),1.98-2.04(m,2H),1.87-1.93(m,2H)；13C NMR(100MHz,CDCl3)ppm:166.9,152.6,145.9,144.7,131.5,129.2(q),127.2(q),125.4,124.3(q),122.7,120.6(q),52.8,26.3,25.6,21.9,21.5；HRMS(EI)Calcd.for C16H14F3NO2:[M+],309.0977.Found:m/z 309.0964.
Wherein the chemical structural general formula of the 2-trifluoromethyl-7, 8,9, 10-tetrahydrophenanthridine-6-carboxylic acid methyl ester is as follows:
the invention develops a method for synthesizing quinoline derivatives by using aniline, electron-withdrawing alkyne and ketone of silver trifluoromethanesulfonate catalytic substituent, which is not only suitable for electron-substituted aniline, but also has better yield for electron-withdrawing aniline. The method is a novel method for preparing the substituted quinoline compound, which is simple, convenient, safe, cheap and efficient to operate. Compared with the prior art, the method not only can be suitable for a large number of functional groups, but also has the advantages of simple operation, high yield, single product, convenient separation and purification, safety, low cost and little pollution.
Claims (4)
1. A method for synthesizing quinoline derivatives is characterized by comprising the following steps:
in a reaction vessel, the molar ratio of 1: 1: 1.2-2 in sequenceAdding aromatic amine I, electron-withdrawing alkyne II and ketone III, adding a solvent according to the proportion that 1mmol of aromatic amine is added into 2-4 mL, and then adding a catalyst copper trifluoromethanesulfonate Cu (OTf)2And an additive of trifluoromethanesulfonic acid (HOTf), the addition amounts of which are respectively 0.8-5% and 1.8-10% of the molar amount of the aromatic amine, reacting for 10-24 h under the condition of an oil bath at 100-120 ℃, cooling to room temperature, adding water, extracting for three times by using ethyl acetate, combining organic layers, concentrating under reduced pressure, and purifying the product by column chromatography to obtain the product of the quinoline derivative, wherein the reaction general formula of the synthetic method is as follows:
the chemical structural general formula of the quinoline derivative synthesized by the method is as follows:
wherein R is1Is H, C1～C6 Chain alkyl, C1～C6Chain alkoxy group, NO2OH, F, Cl or Br; the ketone III is 2-acetylpyridine, o-fluoro acetophenone, m-fluoro acetophenone, p-fluoro acetophenone, o-chloro acetophenone, m-chloro acetophenone, p-chloro acetophenone, o-bromo acetophenone, m-bromo acetophenone, p-bromo acetophenone, o-methoxy acetophenone, m-methoxy acetophenone, p-methoxy acetophenone, o-methyl acetophenone, m-methyl acetophenone, p-methyl acetophenone, 2-acetyl thiophene or 2-acetyl pyrrole.
2. The method according to claim 1, wherein the aromatic amine I is aniline, o-fluoroaniline, m-fluoroaniline, p-fluoroaniline, o-chloroaniline, m-chloroaniline, p-chloroaniline, o-bromoaniline, m-bromoaniline, p-bromoaniline, o-nitroaniline, m-nitroaniline, p-nitroaniline, o-methoxyaniline, m-methoxyaniline, p-methoxyaniline, o-methylaniline, m-methylaniline or p-methylaniline.
3. A process for the synthesis of quinoline derivatives according to claim 1, characterized in that the solvent is toluene, acetonitrile or THF.
4. The method for synthesizing quinoline derivatives according to claim 1, wherein the column chromatography conditions are as follows: a 300-400 mesh silica gel column, wherein the eluent is a mixture of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 2-1: 10.
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