CN106366035B - Synthesis method of quinoline derivative - Google Patents

Synthesis method of quinoline derivative Download PDF

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CN106366035B
CN106366035B CN201610763526.4A CN201610763526A CN106366035B CN 106366035 B CN106366035 B CN 106366035B CN 201610763526 A CN201610763526 A CN 201610763526A CN 106366035 B CN106366035 B CN 106366035B
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ethyl acetate
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张旭
徐学锋
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Nanyang Normal 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
    • C07D215/16—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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • 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
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Abstract

The invention provides a method for synthesizing a quinoline derivative, which comprises the following steps of: 1: 1.2-4 sequentially adding aromatic amine, electron-withdrawing alkyne and alkyne, adding a solvent according to the proportion that 1mmol of aromatic amine is added into 2-4 mL of the solvent, then adding a catalyst AgOTf (silver trifluoromethanesulfonate) and an additive HOTf (trifluoromethanesulfonic acid), wherein the addition amounts are 0.8-5% and 1.8-10% of the molar amount of the aromatic amine respectively, reacting for 8-24 h under the condition of an oil bath at 100-120 ℃, cooling to room temperature, adding water, extracting with ethyl acetate for three times, 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

Synthesis method of quinoline derivative
Technical Field
The invention relates to a quinoline derivative, in particular to a synthesis method of 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 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 glycerol as raw materialsHeating the oil and mild oxidant together to obtain the quinoline derivative. 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, wherein nitrobenzene or arsenic acid is commonly used as a catalyst method. However, the reaction is carried out in concentrated sulfuric acid at high temperature, and in the Combes synthesis method, the aromatic amine and the beta-diketone are condensed into 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. However, existing methods for synthesizing quinoline derivatives are ubiquitous: needs active reaction substrates, has low reaction rate, long reaction time, more and more byproducts, is difficult to treat, has too single reaction form (causes the synthesized product to have great limitation), and the like. 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 synthesis of quinoline derivatives, the technical problem to be solved by the invention is to provide a synthesis method of quinoline derivatives, 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 for synthesizing quinoline derivatives, comprising the following method steps:
in a reaction vessel, the molar ratio of 1: 1: 1.2-4 sequentially adding aromatic amine I, electron-withdrawing alkyne II and alkyne III, adding a solvent according to the proportion that 1mmol of aromatic amine is added into 2-4 mL of the solvent, then adding a catalyst AgOTf (silver trifluoromethanesulfonate) and an additive HOTf (trifluoromethanesulfonic acid), wherein the addition amounts are 0.8-5% and 1.8-10% of the molar amount of the aromatic amine respectively, reacting for 8-24 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 a product by column chromatography to obtain a product quinoline derivative, wherein the reaction general formula of the synthetic method is as follows:
Figure BDA0001100146860000041
the chemical structural general formula of the quinoline derivative synthesized by the method is as follows:
Figure BDA0001100146860000042
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 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 alkyne III is phenylacetylene, o-fluorophenylacetylene, m-fluorophenylacetylene, p-fluorophenylacetylene, o-chlorophenylacetylene, m-chlorophenylacetylene, p-chlorophenylacetylene, o-bromophenylacetylene, m-bromophenylacetylene, p-bromophenylacetylene, o-methoxyphenylacetylene, m-methoxyphenylacetylene, p-methoxyphenylacetylene, o-methylphenylacetylene, m-methylphenylacetylene, o-trifluorophenylacetylene, m-trifluorophenylacetylene, p-trifluorophenylacetylene, 1-pentyne, 1-hexyne, 1-heptyne, 2-ethynylthiophene or 2-ethynylpyrrole.
The solvent is toluene, methanol, THF or 1, 2-dichloroethane.
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: 10-1: 5.
The invention adopts the technical scheme to design a method for synthesizing the quinoline derivative, and 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. 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-phenylquinoline-2-carboxylic acid methyl ester1H NMR profile;
FIG. 2 shows the preparation of the compound 4-phenylquinoline-2-carboxylic acid methyl ester13C NMR characterization chart.
Detailed Description
The synthesis of a quinoline derivative according to the present invention is described in detail with reference to the following examples.
Example 1
A synthetic method of 4-phenylquinoline-2-methyl formate comprises the following steps:
1.0mmol (93mg) of aniline, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf and 2mL of solvent hexanenitrile are added in sequence in a reaction vessel, reacted in an oil bath at 100 ℃ for 8h, cooled to room temperatureAdding 5mL of water, extracting with ethyl acetate for 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 1:10 to obtain 235.1mg of a white solid product, wherein the yield is 89%, and the purity is 99.9%.1H NMR(400MHz,CDCl3)δppm:8.38(d,J＝8.8Hz,1H),8.16(s,1H),7.98(d,J＝8.8Hz,1H),7.77-7.81(t,1H),7.53-7.62(m,6H),4.10(s,3H)；13C NMR(100MHz,CDCl3)δppm:166.0,149.9,148.2,147.5,137.5,131.1,130.1,129.6,128.8,128.7,128.7,127.9,125.8,121.3,53.2；HRMS(ESI-TOF)m/z calcd for C17H14NO2[M+H]+264.1019,found 264.0985.
Wherein the chemical structural general formula of the quinoline-2, 4-methyl dicarboxylate is as follows:
Figure BDA0001100146860000061
example 2
A synthetic method of 6-fluoro-4-phenylquinoline-2-methyl formate comprises the following steps:
adding para-fluoroaniline 1.0mmol (111mg), butynedioic acid dimethyl ester 1.0mmol (142.1mg), phenylacetylene 1.2mmol (122.4mg), catalyst AgOTf 0.005mmol (1.3mg), HOTf 0.01mmol (1.5mg), solvent hexanitrile 2mL into a reaction vessel in sequence, reacting in an oil bath at 120 ℃ for 12h, cooling to room temperature, adding water 5mL, 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, using a mixture of ethyl acetate and petroleum ether as eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:10, and obtaining a white solid product 220.0mg, the yield is 78%, and the purity is 99.9%.1H NMR(400MHz,CDCl3)δppm:7.38(d,J＝8.8Hz,1H),8.17(s,1H),7.52-7.54(m,7H),4.09(s,3H)；13C NMR(100MHz,CDCl3)δppm:165.8,163.2,160.7,149.4(d,J＝5.7),146.9,145.3,137.0,133.7(d,J＝9.5),129.3,129.0,128.9,121.8,120.5(d,J＝25.9),109.2(d,J＝23.3),53.2；HRMS(ESI-TOF)m/z calcd for C17H13FNO2[M+H]+282.0925,found 282.0857.
Wherein the chemical structural general formula of the methyl 6-fluoro-4-phenylquinoline-2-carboxylate is as follows:
Figure BDA0001100146860000071
example 3
A synthetic method of 6-chloro-4-phenylquinoline-2-methyl formate comprises the following steps:
adding 1.0mmol (127mg) of parachloroaniline, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf solvent and 2mL of hexanenitrile in a reaction vessel in turn, reacting in an oil bath at 100 ℃ for 12h, cooling to room temperature, adding 5mL of water, extracting with ethyl acetate for 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 241.4mg of a white solid product, wherein the yield is 81 percent and the purity is 99.9 percent.1H NMR(400MHz,CDCl3)δppm:8.31(d,J＝9.2Hz,1H),8.17(s,1H),7.95(s,1H),7.74(d,J＝8.8Hz,1H),7.51-7.60(m,5H),4.10(s,3H)；13C NMR(100MHz,CDCl3)δppm:165.7,149.2,147.6,146.6,136.8,135.0,132.7,131.2,129.4,129.1,128.9,128.5,124.6,122.1,53.3；HRMS(ESI-TOF)m/z calcd for C17H13ClNO2[M+H]+298.0629,found 298.0577.
Wherein the chemical structural general formula of the methyl 6-chloro-4-phenylquinoline-2-carboxylate is as follows:
Figure BDA0001100146860000081
example 4
A synthetic method of 6-bromo-4-phenylquinoline-2-methyl formate comprises the following steps:
to a reaction vessel were added p-bromoaniline 1.0mmol (171mg), butynedioic acid dimethyl ester 1.0mmol (142.1mg), phenylacetylene1.2mmol (122.4mg), 0.005mmol (1.3mg) of catalyst AgOTf, 0.01mmol (1.5mg) of HOTf, 2mL of solvent hexanenitrile, reaction in an oil bath at 100 ℃ for 12h, cooling to room temperature, adding 5mL of water, extracting with ethyl acetate for three times, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-400-mesh silica gel column as eluent, wherein the mixture of ethyl acetate and petroleum ether has a volume ratio of 1:10 to obtain 270.2mg of white solid product, the yield is 79%, and the purity is 99.9%.1H NMR(400MHz,CDCl3)δppm:8.24(d,J＝8.8Hz,1H),8.17(s,1H),8.12(s,1H),7.87(d,J＝8.8Hz,1H),7.51-7.56(m,5H),4.10(s,3H)；13C NMR(100MHz,CDCl3)δppm:165.7,149.2,147.8,146.7,136.8,133.8,132.7,129.5,129.1,129.0,128.9,128.0,123.4,122.1,53.3；HRMS(ESI-TOF)m/z calcd for C17H13BrNO2[M+H]+342.0124,found 342.0066.
Wherein the chemical structural general formula of the methyl 6-bromo-4-phenylquinoline-2-carboxylate is as follows:
Figure BDA0001100146860000091
example 5
A synthetic method of 6-methyl-4-phenylquinoline-2-methyl formate comprises the following steps:
1.0mmol (107mg) of p-methylaniline, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf solvent and 2mL of hexanenitrile are sequentially added into a reaction vessel, reacted for 8 hours in an oil bath at 100 ℃, cooled to room temperature, added with 5mL of water, extracted with ethyl acetate for three times, combined organic layers and concentrated under reduced pressure, and the product is purified by column chromatography, namely a 300-mesh 400-mesh silica gel column, and an eluent is a mixture of ethyl acetate and petroleum ether, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:10, so that 261.4mg of a white solid product is obtained, the yield is 94%, and the purity is 99..1H NMR(400MHz,CDCl3)δppm:8.26(d,J＝8.4Hz,1H),8.12(s,1H),7.72(s,1H),7.63(d,J＝8.4Hz,1H),7.52-7.55(m,5H),4.08(s,3H),2.50(s,3H)；13C NMR(100MHz,CDCl3)δppm:166.2,149.1,146.8,146.6,139.1,137.7,132.4,130.8,129.5,128.7,128.6,127.9,124.4,121.4,53.1,22.0；HRMS(ESI-TOF)m/z calcd for C18H16NO2[M+H]+278.1176,found 278.1183.
Wherein the chemical structural general formula of the methyl 6-methyl-4-phenylquinoline-2-carboxylate is as follows:
Figure BDA0001100146860000101
example 6
A synthetic method of 6-methoxy-4-phenylquinoline-2-methyl formate comprises the following steps:
adding 1.0mmol (123.1mg) of p-anisidine, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf and 2mL of solvent hexanitrile into a reaction vessel in turn, reacting in an oil bath at 100 ℃ for 8h, cooling to room temperature, adding 5mL of water, extracting with ethyl acetate for 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, wherein the volume ratio of the two is 1:10, so as to obtain 241.2mg of a white solid product, the yield is 82%, and the purity is 99.9%.1H NMR(400MHz,CDCl3)δppm:8.27(d,J＝9.6Hz,1H),8.11(s,1H),7.51-7.55(m,5H),7.44(s,1H),7.23(d,J＝9.2Hz,1H),4.08(s,3H),3.81(s,3H)；13C NMR(100MHz,CDCl3)δppm:166.2,159.6,148.1,145.1,144.3,137.9,132.7,129.3,129.3,128.8,128.7,122.9,121.8,103.4,55.5,53.1；HRMS(ESI-TOF)m/z calcd for C18H16NO3[M+H]+294.1125,found 294.1129.
Wherein the chemical structural general formula of the methyl 6-methoxy-4-phenylquinoline-2-carboxylate is as follows:
Figure BDA0001100146860000111
example 7
A synthetic method of 7-fluoro-4-phenylquinoline-2-methyl formate comprises the following steps:
adding m-fluoroaniline 1.0mmol (111mg), butynedioic acid dimethyl ester 1.0mmol (142.1mg), phenylacetylene 1.2mmol (122.4mg), catalyst AgOTf 0.005mmol (1.3mg), HOTf 0.01mmol (1.5mg), solvent hexanitrile 2mL into a reaction vessel in turn, reacting in an oil bath at 110 ℃ for 12h, cooling to room temperature, adding water 5mL, 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, using a mixture of ethyl acetate and petroleum ether as eluent, wherein the volume ratio of the two is 1:10, and obtaining a white solid product 203.2mg, the yield is 72%, and the purity is 99.9%.1H NMR(400MHz,CDCl3)δppm:8.12(s,1H),7.97-8.02(m,2H),7.51-7.56(m,5H),7.37-7.41(t,1H),4.10(s,3H)；13C NMR(100MHz,CDCl3)δppm:165.8,164.5,162.0,150.2,149.3(d,J＝12.8),148.5,137.2,129.5,129.0,128.1(d,J＝9.6),125.0,120.8,119.2(d,J＝25.0),114.4(d,J＝20.4),53.3；HRMS(ESI-TOF)m/z calcd for C17H13FNO2[M+H]+282.0925,found 282.0928.
Wherein the chemical structural general formula of the 7-fluoro-4-phenylquinoline-2-methyl formate is as follows:
Figure BDA0001100146860000121
example 8
A synthetic method of 7-chloro-4-phenylquinoline-2-methyl formate comprises the following steps:
adding 1.0mmol (161mg) of m-chloroaniline, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf solvent and 2mL of hexanenitrile in a reaction vessel in sequence, reacting in an oil bath at 100 ℃ for 24 hours, cooling to room temperature, adding 5mL of water, extracting with ethyl acetate for three times, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-mesh 400-mesh silica gel column, using a mixture of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:10, and obtaining 220.6mg of a white solid product, the yield is 74%, and the purity is 99.9%.1H NMR(400MHz,CDCl3)δppm:8.33(d,J＝8.0Hz,1H),8.09(s,1H),7.64-7.71(m,2H),7.28-7.44(m,5H),4.08(s,3H)；13C NMR(100MHz,CDCl3)δppm:165.5,150.0,149.6,147.1,140.2,131.5,130.9,130.9,129.7,128.9,128.1,127.7,125.6,124.7,53.3；HRMS(ESI-TOF)m/z calcd for C17H13ClNO2[M+H]+298.0629,found 298.0576.
Wherein the chemical structural general formula of the 7-chloro-4-phenylquinoline-2-methyl formate is as follows:
Figure BDA0001100146860000122
example 9
A synthetic method of 7-methyl-4-phenylquinoline-2-methyl formate comprises the following steps:
adding 1.0mmol (107mg) of m-methylaniline, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf solvent and 2mL of hexanenitrile in a reaction vessel in turn, reacting in an oil bath at 100 ℃ for 8 hours, cooling to room temperature, adding 5mL of water, extracting with ethyl acetate for three times, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-mesh 400-mesh silica gel column, using a mixture of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:10, and obtaining 233.6mg of a white solid product, the yield is 84%, and the purity is 99.9%.1H NMR(400MHz,CDCl3)δppm:8.16(s,1H),8.09(s,1H),7.87(d,J＝8.8Hz,1H),7.51-7.56(m,5H),7.43(d,J＝9.2Hz,1H),4.08(s,3H),2.58(s,3H)；13C NMR(100MHz,CDCl3)δppm:166.2,149.6,148.4,147.4,140.5,137.7,131.0,130.0,129.5,128.7,128.7,125.9,125.4,120.6,53.1,21.7；HRMS(ESI-TOF)m/z calcd for C18H16NO2[M+H]+278.1176,found 278.1126.
Wherein the chemical structural general formula of the 7-methyl-4-phenylquinoline-2-methyl formate is as follows:
Figure BDA0001100146860000131
example 10
A synthetic method for preparing 7-methoxy-4-phenylquinoline-2-methyl formate comprises the following steps:
adding 1.0mmol (123.1mg) of m-methoxyaniline, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf solvent and 2mL of acetonitrile into a reaction vessel in sequence, reacting in an oil bath at 100 ℃ for 8h, cooling to room temperature, adding 5mL of water, extracting with ethyl acetate for three times, 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 a white solid product of 232.4mg, 79 percent of yield and 99.9 percent of purity.1H NMR(400MHz,CDCl3)δppm:8.03(s,1H),7.82-7.86(t,1H),7.67(s,1H),7.50-7.54(m,5H),7.21-7.30(m,1H),4.08(s,3H),3.96(s,3H)；13C NMR(100MHz,CDCl3)δppm:166.7,161.0,150.1,149.6,147.6,137.6,129.5,128.7,128.6,126.7,123.1,122.1,119.5,108.5,55.7,53.1；HRMS(ESI-TOF)m/zcalcd for C18H16NO3[M+H]+294.1125,found 294.1123.
Wherein the chemical structural general formula of the 7-methoxy-4-phenylquinoline-2-methyl formate is as follows:
Figure BDA0001100146860000141
example 11
A synthetic method for preparing 8-fluoro-4-phenylquinoline-2-methyl formate comprises the following steps:
sequentially adding 1.0mmol (111mg) of o-fluoroaniline, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf and 2mL of solvent hexanenitrile in a reaction vessel, reacting in an oil bath at 120 ℃ for 24h, cooling to room temperature, adding 5mL of water, extracting with ethyl acetate for three times, combining organic layers, concentrating under reduced pressure, purifying a product by column chromatography300-400 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 1:5, so that 180.5mg of a white solid product is obtained, the yield is 64 percent, and the purity is 99.9 percent.1H NMR(400MHz,CDCl3)δppm:8.20(s,1H),7.76(d,J＝8.4Hz,1H),7.45-7.53(m,7H),4.08(s,3H)；13C NMR(100MHz,CDCl3)δppm:165.7,159.9,157.3,150.0,147.6,138.6(d,J＝11.6),137.1,129.5,129.0,128.8,128.4(d,J＝8.1),122.1,121.5(d,J＝4.8),114.1(d,J＝81.2),53.2；HRMS(ESI-TOF)m/z calcd forC17H13FNO2[M+H]+282.0925,found 282.0927.
Wherein the chemical structural general formula of the 8-fluoro-4-phenylquinoline-2-methyl formate is as follows:
Figure BDA0001100146860000151
example 12
A synthetic method for preparing 8-chloro-4-phenylquinoline-2-methyl formate comprises the following steps:
1.0mmol (127mg) of o-chloroaniline, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf and 2mL of solvent hexanitrile are sequentially added into a reaction vessel, the mixture is reacted in an oil bath at 110 ℃ for 8 hours, cooled to room temperature, added with 5mL of water, extracted with ethyl acetate for three times, combined with organic layers, concentrated under reduced pressure, purified by column chromatography, and purified by a 300-mesh 400-mesh silica gel column, wherein an eluent is a mixture of ethyl acetate and petroleum ether, the volume ratio of the two is 1:10, and the white solid product is 220.6mg, the yield is 74 percent and the purity is 99.9 percent.1H NMR(400MHz,CDCl3)δppm:8.20(s,1H),7.89-7.92(t,2H),7.48-7.54(m,6H),4.09(s,3H)；13C NMR(100MHz,CDCl3)δppm:165.8,150.7,147.9,144.6,137.2,135.2,130.3,129.6,129.3,129.0,128.8,128.3,125.0,122.1,53.3；HRMS(ESI-TOF)m/z calcd for C17H13ClNO2[M+H]+298.0629,found 298.0635.
Wherein the chemical structural general formula of the 8-chloro-4-phenylquinoline-2-methyl formate is as follows:
Figure BDA0001100146860000161
example 13
A synthetic method for preparing 8-methyl-4-phenylquinoline-2-methyl formate comprises the following steps:
1.0mmol (1107mg) of o-toluidine, 1.0mmol (142.1mg) of dimethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf and 2mL of nitrile solvent are sequentially added into a reaction vessel, the mixture is reacted in an oil bath at 100 ℃ for 8 hours, cooled to room temperature, added with 5mL of water, extracted with ethyl acetate for three times, combined with organic layers, concentrated under reduced pressure, purified by column chromatography, purified by a 300-mesh 400-mesh silica gel column, and eluent is a mixture of ethyl acetate and petroleum ether, the volume ratio of the two is 1:10, so that 233.6mg of a white solid product is obtained, the yield is 84%, and the purity is 99.9%.1H NMR(400MHz,CDCl3)1H NMR(400MHz,CDCl3)δppm:8.11(s,1H),7.79(d,J＝8.4Hz,1H),7.63(d,J＝6.8Hz,1H),7.45-7.51(m,6H),4.06(s,3H),2.94(s,3H)；13C NMR(100MHz,CDCl3)δppm:166.3,149.9,147.4,146.3,139.1,138.0,130.2,129.6,128.6,128.6,128.3,127.9,123.7,121.1,52.9,18.3；HRMS(ESI-TOF)m/z calcd for C18H16NO2[M+H]+278.1176,found 278.1174.
Wherein the general formula of the preparation chemical structure of the 8-methyl-4-phenylquinoline-2-methyl formate is as follows:
Figure BDA0001100146860000171
example 14
A synthetic method for preparing 7-methoxy-2, 4-diphenyl quinoline comprises the following steps:
1.0mmol (123.1mg) of m-methoxyaniline, 1.0mmol (160.2mg) of methyl phenylpropargyrate, 1.2mmol (122.4mg) of phenylacetylene and 0.005mmol (1) of catalyst AgOTf are sequentially added into a reaction vessel.3mg), 0.01mmol (1.5mg) of HOTf, 2mL of solvent hexanenitrile, reacting in 100 ℃ oil bath for 8h, cooling to room temperature, adding 5mL of water, extracting with ethyl acetate for three times, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, purifying with a 300-400-mesh silica gel column, and eluting with a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:5 to obtain 296.4mg of white solid product with a yield of 95% and a purity of 99.9%.1H NMR(400MHz,CDCl3)1H NMR(400MHz,CDCl3)δppm: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)δppm: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:
Figure BDA0001100146860000181
example 15
A synthetic method for preparing 7-trifluoromethyl-2, 4-diphenylquinoline comprises the following steps:
adding 1.0mmol (161.1mg) of m-trifluoromethylaniline, 1.0mmol (160.2mg) of methyl phenylpropargyl formate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf and 2mL of solvent hexanenitrile in a reaction vessel in sequence, reacting in an oil bath at 120 ℃ for 24h, cooling to room temperature, adding 5mL of water, extracting for three times by using ethyl acetate, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 400-mesh silica gel column with 300 meshes as an eluent, using a mixture of ethyl acetate and petroleum ether, wherein the volume ratio of the two is 1:5, and obtaining 287.1mg of a white solid product, the yield is 82%, and the purity is 99.9%.1H NMR(400MHz,CDCl3)δppm: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)δppm: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:
Figure BDA0001100146860000191
example 16
A synthetic method for preparing 2-methyl-6-methoxy-4-phenylquinoline comprises the following steps:
adding 1.0mmol (123.1mg) of p-anisidine, 1.0mmol (98.1mg) of methyl butynoate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf and 2mL of solvent hexanitrile into a reaction vessel in sequence, reacting in an oil bath at 100 ℃ for 8h, cooling to room temperature, adding 5mL of water, extracting for three times by using 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 182.6mg of a white solid product, wherein the yield is 73 percent and the purity is 99.9 percent.1H NMR(400MHz,CDCl3)δppm: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)δppm: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:
Figure BDA0001100146860000201
example 17
A synthetic method for preparing 6-methyl-4-phenylquinoline-2-ethyl formate comprises the following steps:
adding 1.0mmol (123.1mg) of p-methylaniline, 1.0mmol (170.1mg) of diethyl butynedioate, 1.2mmol (122.4mg) of phenylacetylene, 0.005mmol (1.3mg) of AgOTf catalyst, 0.01mmol (1.5mg) of HOTf and 2mL of solvent hexanitrile into a reaction vessel in turn, reacting in an oil bath at 80 ℃ for 8h, cooling to room temperature, adding 5mL of water, extracting for three times by using ethyl acetate, combining organic layers, concentrating under reduced pressure, purifying the product by column chromatography, using a 300-mesh 400-mesh silica gel column, using a mixture of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:10, and obtaining 277.5mg of a white solid product, the yield is 95%, and the purity is 99.9%.1H NMR(400MHz,CDCl3)δppm:8.27(d,J＝7.6Hz,1H),8.10(s,1H),7.70(s,1H),7.61(d,J＝8.4Hz,1H),7.50-7.57(m,5H),4.53-4.58(q,2H),2.49(s,3H),1.47-1.50(t,3H)；13C NMR(100MHz,CDCl3)δppm:165.6,149.0,146.9,146.8,139.0,137.8,132.4,130.8,129.5,128.7,128.6,127.8,124.4,121.4,62.2,22.0,14.4；HRMS(ESI-TOF)m/z calcd for C19H18NO2[M+H]+292.1332,found 292.1291.
Wherein the general formula of the preparation chemical structure of the 6-methyl-4-phenylquinoline-2-ethyl formate is as follows:
Figure BDA0001100146860000211
the invention develops a method for synthesizing quinoline derivatives by utilizing aniline, electron-withdrawing alkyne and alkyne of silver trifluoromethanesulfonate catalytic substituent, which is not only suitable for aniline for electron substitution, 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 (5)

1. A method for synthesizing quinoline derivatives is characterized by comprising the following steps:
in a reaction vessel, the molar ratio of 1: 1: 1.2-4 sequentially adding aromatic amine I, electron-withdrawing alkyne II and alkyne III, adding a solvent according to the proportion that 1mmol of aromatic amine is added into 2-4 mL of the solvent, then adding a catalyst silver triflate AgOTf and an additive triflate HOTf, wherein the addition amounts are 0.8-5 percent and 1.8-10 percent of the molar amount of the aromatic amine respectively, reacting for 8-24 hours 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 a product by column chromatography to obtain a product quinoline derivative, wherein the reaction general formula of the synthetic method is as follows:
Figure FDA0002953376980000011
the chemical structural general formula of the quinoline derivative synthesized by the method is as follows:
Figure FDA0002953376980000012
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 C3～C6Alkyl, cycloalkyl, thienyl, aryl.
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. The method as claimed in claim 1, wherein the electron-withdrawing alkyne II is dimethyl butynedioate, methyl phenylpropionate, methyl propiolate or methyl butynoate.
4. The method for synthesizing a quinoline derivative according to claim 1, wherein the alkyne iii is phenylacetylene, 1-pentyne, 1-hexyne, 1-heptyne, or 2-ethynylthiophene.
5. 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: 10-1: 5.
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