CN106380446A - Synthesis method of quinoline-2-formic acid ester derivatives - Google Patents

Synthesis method of quinoline-2-formic acid ester derivatives Download PDF

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CN106380446A
CN106380446A CN201610785206.9A CN201610785206A CN106380446A CN 106380446 A CN106380446 A CN 106380446A CN 201610785206 A CN201610785206 A CN 201610785206A CN 106380446 A CN106380446 A CN 106380446A
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quinoline
synthetic method
formic acid
aniline
aromatic amine
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CN106380446B (en
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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
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Quinoline Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention provides a synthesis method of quinoline-2-formic acid ester derivatives, wherein the synthesis method comprises the steps: successively adding aromatic amine and electron-withdrawing alkyne into a reaction vessel at a molar ratio of 1:(2-4), adding a solvent according to a ratio of adding 2-4 mL of the solvent to 1 mmol of aromatic amine, then adding a catalyst Cu(OTf)2 and an additive HOTf with the addition amount respectively of 0.8%-5% and 1.8%-10% of the molar amount of aromatic amine, under a condition of 80 DEG C-120 DEG C oil bath, carrying out a reaction for 8-24 h, cooling to room temperature, adding water, extracting for three times with ethyl acetate, merging organic layers, carrying out vacuum concentration, and carrying out column chromatography purification of the products, to obtain the quinoline derivative products. The method has the advantages of cheap reaction substrate, high yield, good selectivity, easy separation and purification, less pollution and simple steps.

Description

A kind of synthetic method of quinoline -2 formic acid esters radical derivative
Technical field
The present invention relates to quinoline is and in particular to a kind of synthetic method of quinoline -2 formic acid esters radical derivative.
Background technology
Quinoline and its derivates are the important organic heterocyclic molecules of a class, are widespread in nature, and widely should For fields such as drug screening, chemical analysis, dye industries.Synthesis of quinoline derivatives method has a lot, mainly has：Skraup- Doebner-Miller synthetic method, Friedlander-Pfitzinge-Combes synthetic method, Bischler-Napieralski Synthetic method (Tetrahedron.Lett, 2000,41,531-533；Org.lett, 2004,6,3965-3968； Eur.J.Org.Chem, 2008,2693-2696 and J.Org.Chem, 2003,68,3966-3975), wherein most widely used Be Skraup-Doebner-Miller method.The synthetic method of the quinolines focus that always people study (referring to： G.R.Humphrey,J.T.Kuethe,Chem,Rev,2006,106,2875).Industrial synthesis of quinoline is the most representative at present Method have Skraup synthetic method, heated together with mild oxidizing agent with arylamine, the concentrated sulfuric acid, glycerine, prepared quinoline.? In course of reaction, it is methacrylaldehyde that glycerine is subject to concentrated sulfuric acid effect dehydration at high temperature, then is EEDQ with aniline condensation, after warp Oxidation obtain quinoline, conventional nitrobenzene or arsenic acid as catalyst method, but, this reaction will high temperature be carried out in concentrated sulfuric acid. Combes synthetic method, is to be condensed in sour environment as quinoline ring with aromatic amine and beta-diketon.This method is with arylamine and 1,3- bis- carbonyl Based compound is condensed to yield beta-amino-ketenes, and the latter carries out cyclization in the presence of the concentrated sulfuric acid, obtains quinoline.But, In the presence of having electron withdraw group on arylamine ring, cloud density on phenyl ring can be made to reduce, thus being unfavorable for electrophilic substitution reaction Carrying out.As 1,3- dicarbonyl compound (R1-CO-CH2CO-R2) in R1With R2When different, then the condensation reaction of the first step has Two kinds of possibility, can generate two kinds of beta-amino-ketenes, and cyclised products are the mixture containing two kinds of isomers.
Last century the eighties start to report transition metal-catalyzed terminal alkyne compound and ortho position carries the aniline of halogen First occur coupling reaction to generate adjacent amino alkynes, then be cyclized prepare quinoline method (referring to：(a)Müller,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), be synthesis of quinoline analog derivative important method (referring to:(a)Hartung, C.G.；Breindl,C.；Tillack,A.；Beller,M.Tetrahedron 2000,56,5157；(b)Kawatsura,M.； Hartwig,J.F.J.Am.Chem.Soc.2000,122,9546；(c)Beller,M.；Trauthwein,H.； Eichberger,M.；Breindl,C.；Müller,T.E.Eur.J.Inorg.Chem.1999,11.21；(d) Trauthwein,H.；Tillack,A.；Beller,M.Chem.Commun.1999,2029；(e)Beller,M.； Trauthwein,H.；Eichberger,M.；Breindl,C.；Herwig,J.；Müller,T.E.；Thiel, O.R.Chem.Eur.J.1999,5,1306；(f)Beller,M.；Trauthwein,H.；Eichberger,M.；Breindl, C.；Müller,T.E.；Zapf, A.J.Organomet.Chem.1998,566,277), successfully applied to natural products and In the synthesis of bionical medicine (referring to：Z.Z.Shi,C.Zhang,S.Li,D.l.Pan,S.T.Ding,Y.X.Cui,N.Jiao, Angew.Chem.Int.Ed.2009,48,4572).
Chinese patent CN104151235A discloses a kind of quinoline preparation method, is to be urged using silver trifluoromethanesulfonate Change aniline and ketenes or the olefine aldehydr derivative synthesis of quinoline derivatives of substituent, this patent is simple to operate, can be applied not only to Substantial amounts of functional group, and yield is high, and product is single, is easy to separation and purification, safety is cheap, it is little to pollute.But this patent is still So there are disadvantages that：2,4 upper quinolines for electrophilic ester group can not be prepared.
There are a lot of shortcomings in current synthetic method：Mainly severe reaction conditions, reaction temperature is high, and have needs high temperature High pressure, separates difficult, reaction substrate limiting relatively strong, the quinoline that therefore a kind of method synthesizes substituent is very limited. In addition, utilizing in metal-catalyzed processes, the limited activity of catalyst, these shortcomings cause the operation easier of preparation process to increase, Harm operator's health, environmental pollution is serious.However, the method generally existing of existing synthesis of quinoline derivatives：Need active Reaction substrate, reaction rate is low, the reaction time is longer, how difficult accessory substance is and the form of reaction excessively single (leads to institute The product of synthesis has the shortcomings that significant limitation).In consideration of it, the preparation method of the novel quinoline of research and development seems particularly Important.
Content of the invention
For the defect existing for existing synthesis of quinoline derivatives, the technical problem to be solved is to provide one kind The synthetic method of quinoline -2 formic acid esters radical derivative, the method is simple to operate, and yield is high, and product is single, is easy to separate and purifies.
For solving above-mentioned technical problem, the technical solution used in the present invention is：A kind of quinoline -2 formic acid esters radical derivative Synthetic method, comprise the following steps：
In molar ratio 1 in reaction vessel：2～4 sequentially add aromatic amine I and electrophilic alkynes II, by 1mmol fragrance Race's amine adds the ratio of 2～4mL solvent to add solvent, is subsequently added into catalyst Cu (OTf)2(copper trifluoromethanesulfcomposite), additive HOTf (TFMS), addition be respectively aromatic amine mole 0.8%～5%, 1.8%～10%, 80 DEG C～ React 8～24h under the conditions of 120 DEG C of oil baths, be cooled to room temperature, add water, be extracted with ethyl acetate three times, merge organic layer, decompression Concentrate, product purifies through column chromatography, obtains product quinoline, the reaction expression of its synthetic method is expressed as follows：
The quinoline chemical structure of general formula of synthesis is as follows：
Wherein, R1For-H, C1～C6Chain-like alkyl, C1～C6Chain alkoxyl ,-NO2,-OH, F ,-Br or Cl；R2For- H、C1～C6Chain-like alkyl or phenyl.
Described aromatic amine I is aniline, adjacent fluoroaniline, m-fluoroaniline, para-fluoroaniline, o-chloraniline, m-chloroaniline, right Chloroaniline, o-bromoaniline, m-bromoaniline, para-bromoaniline, ortho-nitraniline, meta nitro aniline, paranitroanilinum, O-methoxy benzene Amine, m-anisidine, P-nethoxyaniline, o-toluidine, m-toluidine, open-chain crown ether, adjacent trifluoromethyl aniline, three Fluoroaniline or to trifluoromethyl aniline.
Described electrophilic alkynes II is dimethyl butyn, diethyl butyn, phenylpropiolic acid methyl esters, phenyl-allylene Acetoacetic ester, Methyl propiolate, tetrolic acid methyl esters, ethyl propiolate or ethyl butyn.
Described solvent is toluene, methyl alcohol, nitrile, THF or 1,2- dichloroethanes.
Described column chromatography condition is：300～400 mesh silicagel columns, eluant, eluent is the mixture of ethyl acetate and petroleum ether, Both volume ratios are 1:10～1:5.
The present invention adopts a kind of synthetic method of quinoline -2 formic acid esters radical derivative designed by technique scheme, and it has Beneficial effect is：
1. present invention acid consumption is few, decreases environmental pollution；
2. reaction substrate of the present invention is simple, wide material sources, is suitable for aniline (the big steric hindrance in inclusion ortho position that various functional groups replace Functional group replace aniline), stereoeffect to reaction impact little.
3. reaction substrate of the present invention is cheap, and yield is high, selectivity is good, easily separated purifying, pollution are few, and step is simply, permissible Omit protection and the deprotection synthesis step of functional group, target product quinoline is widely used in joining of organic chemical reactionses Body, pharmaceutical intermediate and photoelectric material aspect.
Brief description
Fig. 1 represents compound quinoline -2,4- dicarboxylic acid methyl ester1H NMR phenogram；
Fig. 2 represents compound quinoline -2,4- dicarboxylic acid methyl ester13C NMR phenogram.
Specific embodiment
With reference to embodiment, to the present invention, a kind of synthetic method of quinoline -2 formic acid esters radical derivative elaborates.
Embodiment 1
A kind of quinoline -2, the synthetic method of 4- dicarboxylic acid methyl ester, comprise the following steps：
Aniline 1.0mmol (93mg), dimethyl butyn 2.1mmol (298.2mg) is sequentially added in reaction vessel, Catalyst Cu (OAc)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), solvent nitrile 2mL, in 80 DEG C of oil baths Reaction 10h, is cooled to room temperature, add water 5mL, is extracted with ethyl acetate three times, merges organic layer, reduced pressure concentration, product is through post Chromatographic purifying, 300-400 mesh silicagel column, eluant, eluent is the mixture of ethyl acetate and petroleum ether, and both volume ratios are 1:10, obtain To white solid product 223.0mg, yield 91%, purity 99.9%.1H NMR(400MHz,CDCl3)δppm:δ 8.86 (d, J= 8.4Hz, 1H), 8.70 (s, 1H), 8.38 (d, J=8.4Hz, 1H), 7.84-7.88 (t, 1H), 7.76-7.80 (t, 1H), 4.12 (s,3H),4.08(s,3H)；13C NMR(100MHz,CDCl3)δppm:δ166.6,165.3,148.6,147.5,136.0, 131.3,130.6,130.3,126.3,125.5,122.3,53.4,52.9；HRMS(EI)Calcd.for C13H11NO4:[M+], 245.0688.Found:m/z 245.0689.
Wherein, described quinoline -2,4- dicarboxylic acid methyl ester chemical structure of general formula is：
Embodiment 2
A kind of 6- methylquinoline -2, the synthetic method of 4- dicarboxylic acid methyl ester, comprise the following steps：
Open-chain crown ether 1.0mmol (107mg), dimethyl butyn 2.1mmol is sequentially added in reaction vessel (298.2mg), catalyst Cu (OAc)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), solvent nitrile 2mL, React 8h in 80 DEG C of oil baths, be cooled to room temperature, add water 5mL, be extracted with ethyl acetate three times, merge organic layer, reduced pressure concentration, produce Product purify through column chromatography, 300-400 mesh silicagel column, and eluant, eluent is the mixture of ethyl acetate and petroleum ether, both volume ratios For 1:10, obtain white solid product 243.5mg, yield 94%, purity 99.9%.1H NMR(400MHz,CDCl3)δppm:δ 8.63 (d, J=18.4Hz, 2H), 8.25 (d, J=8.4Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 4.10 (s, 3H), 4.07 (s,3H),2.62(s,3H)；13C NMR(100MHz,CDCl3)δppm:δ166.2,165.4,147.3,146.5,141.1, 135.1,132.9,130.9,126.4,124.3,122.4,53.4,52.9,22.3；HRMS(EI)Calcd.for C14H13NO4: [M+],259.0845.Found:m/z 259.0847.
Wherein, described 6- methylquinoline -2,4- dicarboxylic acid methyl ester chemical structure of general formula is：
Embodiment 3
A kind of 6- methoxy quinoline -2, the synthetic method of 4- dicarboxylic acid methyl ester, comprise the following steps：
P-nethoxyaniline 1.0mmol (123.1mg), dimethyl butyn is sequentially added in reaction vessel 2.1mmol (298.2mg), catalyst Cu (OAc)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), solvent is Nitrile 2mL, reacts 8h in 80 DEG C of oil baths, is cooled to room temperature, add water 5mL, is extracted with ethyl acetate three times, merges organic layer, subtracts Pressure concentrates, and product purifies through column chromatography, 300-400 mesh silicagel column, and eluant, eluent is the mixture of ethyl acetate and petroleum ether, and two Person's volume ratio is 1:10, obtain white solid product 253.07mg, yield 92%, purity 99.9%.1H NMR(400MHz, CDCl3)δppm:δ 8.74 (s, 1H), 8.32 (d, J=2.8Hz, 1H), 8.25 (d, J=9.6Hz, 1H), 7.49 (dd, J= 9.2Hz,1H),4.10(s,3H),4.06(s,3H),4.10(s,3H)；13C NMR(100MHz,CDCl3)δppm:δ166.2, 165.5,161.1,145.2,144.6,133.2,132.8,128.5,123.9,103.0,55.8,53.2,52.7；HRMS(EI) Calcd.for C14H13NO5:[M+],275.0794.Found:m/z 275.0796.
Wherein, described 6- methoxy quinoline -2,4- dicarboxylic acid methyl ester chemical structure of general formula is：
Embodiment 4
A kind of 6- fluorine quinoline -2, the synthetic method of 4- dicarboxylic acid methyl ester, comprise the following steps：
Para-fluoroaniline 1.0mmol (111mg), dimethyl butyn 2.1mmol is sequentially added in reaction vessel (298.2mg), catalyst Cu (OAc)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), solvent nitrile 2mL, React 24h in 100 DEG C of oil baths, be cooled to room temperature, add water 5mL, be extracted with ethyl acetate three times, merging organic layer, reduced pressure concentration, Product purifies through column chromatography, 300-400 mesh silicagel column, and eluant, eluent is the mixture of ethyl acetate and petroleum ether, both volumes Than for 1:5, obtain white solid product 226.23mg, yield 86%, purity 99.9%.1H NMR(400MHz,CDCl3)δppm: δ 8.63 (d, J=18.4Hz, 2H), 8.25 (d, J=8.4Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 4.10 (s, 3H), 4.07 (s,3H),2.62(s,3H)；13C NMR(100MHz,CDCl3)δppm:δ165.6,165.1,164.3,161.8,146.9, 145.9,135.1,133.9 (d, J=10Hz), 127.6 (d, J=11Hz), 123.3,121.2 (d, J=26Hz), 109.7 (d, ), J=25Hz 53.4,53.0；HRMS(EI)Calcd.for C13H10FNO4:[M+],263.0594.Found:m/z 263.0591.
Wherein, described 6- fluorine quinoline -2,4- dicarboxylic acid methyl ester chemical structure of general formula is：
Embodiment 5
A kind of 6- chloroquinoline -2, the synthetic method of 4- dicarboxylic acid methyl ester, comprise the following steps：
Parachloroanilinum 1.0mmol (127mg), dimethyl butyn 2.1mmol is sequentially added in reaction vessel (298.2mg), catalyst Cu (OAc)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), solvent nitrile 2mL, React 24h in 100 DEG C of oil baths, be cooled to room temperature, add water 5mL, be extracted with ethyl acetate three times, merging organic layer, reduced pressure concentration, Product purifies through column chromatography, 300-400 mesh silicagel column, and eluant, eluent is the mixture of ethyl acetate and petroleum ether, both volumes Than for 1:10, obtain white solid product 245.53mg, yield 88%, purity 99.9%.1H NMR(400MHz,CDCl3)δ ppm:δ 8.76 (s, 1H), 8.62 (dd, J=10.4Hz, 1H), 8.38 (dd, J=9.6,9.2Hz, 1H), 7.63 (m, 1H), 4.12(s,3H),4.08(s,3H)；13C NMR(100MHz,CDCl3)δppm:δ165.5,165.0,147.7,147.0, 137.0,134.9,132.6,131.7,126.9,124.7,123.3,53.4,53.0；HRMS(EI)Calcd.for C13H10ClNO4:[M+],279.0298.Found:m/z 279.0297.
Wherein, described 6- chloroquinoline -2,4- dicarboxylic acid methyl ester chemical structure of general formula is：
Embodiment 6
A kind of 6- bromoquinoline -2, the synthetic method of 4- dicarboxylic acid methyl ester, comprise the following steps：
Para-bromoaniline 1.0mmol (171mg), dimethyl butyn 2.1mmol is sequentially added in reaction vessel (298.2mg), catalyst Cu (OAc)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), solvent nitrile 2mL, React 24h in 100 DEG C of oil baths, be cooled to room temperature, add water 5mL, be extracted with ethyl acetate three times, merging organic layer, reduced pressure concentration, Product purifies through column chromatography, 300-400 mesh silicagel column, and eluant, eluent is the mixture of ethyl acetate and petroleum ether, both volumes Than for 1:10, obtain white solid product 284.23mg, yield 88%, purity 99.9%.1H NMR(400MHz,CDCl3)δ ppm:δ 9.12 (d, J=2.4Hz, 2H), 8.73 (s, 1H), 8.22 (d, J=9.2Hz, 1H), 7.93 (dd, J=9.2,8.8Hz, 1H),4.12(s,3H),4.08(s,3H)；13C NMR(100MHz,CDCl3)δppm:δ165.5,165.0,147.8,147.2, 134.8,134.3,132.6,128.0,127.2,125.6,123.2,53.5,53.1；HRMS(EI)Calcd.for C13H10BrNO4:[M+],322.9793.Found:m/z 322.9796.
Wherein, described 6- bromoquinoline -2,4- dicarboxylic acid methyl ester chemical structure of general formula is：
Embodiment 7
A kind of 6- Trifluoromethylquinocarboxylic -2, the synthetic method of 4- dicarboxylic acid methyl ester, comprise the following steps：
P-trifluoromethylaniline 1.0mmol (161mg), dimethyl butyn is sequentially added in reaction vessel 2.1mmol (298.2mg), catalyst Cu (OAc)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), solvent is Nitrile 2mL, reacts 24h in 120 DEG C of oil baths, is cooled to room temperature, add water 5mL, is extracted with ethyl acetate three times, merges organic layer, Reduced pressure concentration, product purifies through column chromatography, 300-400 mesh silicagel column, and eluant, eluent is the mixture of ethyl acetate and petroleum ether, Both volume ratios are 1:5, obtain white solid product 247.33mg, yield 79%, purity 99.9%.1H NMR(400MHz, CDCl3)δppm:δ 8.63 (d, J=18.4Hz, 2H), 8.25 (d, J=8.4Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 4.10 (s,3H),4.07(s,3H),2.62(s,3H)；13C NMR(100MHz,CDCl3)δppm:δ165.2,164.8,149.6, (q, J=10Hz), 149.4,136.7,132.3,131.5 126.3 (q, J=11Hz), 125.4 (q, J=8.8Hz), 125.0, 123.8 (q, J=9.2,8.8Hz), 123.4,53.4,53.0；HRMS(EI)Calcd.for C14H10F3NO4:[M+], 313.0562.Found:m/z 313.0564.
Wherein, described 6- Trifluoromethylquinocarboxylic -2,4- dicarboxylic acid methyl ester chemical structure of general formula is：
Embodiment 8
A kind of 6- Trifluoromethylquinocarboxylic -2, the synthetic method of 4- dicarboxylic acid methyl ester, comprise the following steps：
P-trifluoromethylaniline 1.0mmol (161mg), dimethyl butyn is sequentially added in reaction vessel 2.1mmol (298.2mg), catalyst Cu (OAc)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), solvent is Nitrile 2mL, reacts 24h in 120 DEG C of oil baths, is cooled to room temperature, add water 5mL, is extracted with ethyl acetate three times, merges organic layer, Reduced pressure concentration, product purifies through column chromatography, 300-400 mesh silicagel column, and eluant, eluent is the mixture of ethyl acetate and petroleum ether, Both volume ratios are 1:5, obtain white solid product 247.33mg, yield 79%, purity 99.9%.1H NMR(400MHz, CDCl3)δppm:δ 8.63 (d, J=18.4Hz, 2H), 8.25 (d, J=8.4Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 4.10 (s,3H),4.07(s,3H),2.62(s,3H)；13C NMR(100MHz,CDCl3)δppm:δ165.2,164.8,149.6, (q, J=10Hz), 149.4,136.7,132.3,131.5 126.3 (q, J=11Hz), 125.4 (q, J=8.8Hz), 125.0, 123.8 (q, J=9.2,8.8Hz), 123.4,53.4,53.0；HRMS(EI)Calcd.for C14H10F3NO4:[M+], 313.0562.Found:m/z 313.0564.
Wherein, described 6- Trifluoromethylquinocarboxylic -2,4- dicarboxylic acid methyl ester chemical structure of general formula is：.
Embodiment 9
A kind of synthetic method of the preparation of 2,4- diphenylquinoline, comprises the following steps：
Sequentially add aniline 1.0mmol (97mg), phenylpropiolic acid methyl esters 2.1mmol (336.4mg) in reaction vessel, urge Agent Cu (OAc)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), solvent nitrile 2mL, in 100 DEG C of oil baths Reaction 18h, is cooled to room temperature, add water 5mL, is extracted with ethyl acetate three times, merges organic layer, reduced pressure concentration, product is through post Chromatographic purifying, 300-400 mesh silicagel column, eluant, eluent is the mixture of ethyl acetate and petroleum ether, and both volume ratios are 1:5, obtain To white solid product 278.62mg, yield 89%, purity 99.9%.1H NMR(400MHz,CDCl3)δppm:δ8.63(d,J =18.4Hz, 2H), 8.25 (d, J=8.4Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 4.10 (s, 3H), 4.07 (s, 3H), 2.62(s,3H)；13C NMR(100MHz,CDCl3)δppm:δ165.2,164.8,149.6,149.4,136.7,132.3, 131.5 (q, J=10Hz), 126.3 (q, J=11Hz), 125.4 (q, J=8.8Hz), 125.0,123.8 (q, J=9.2, 8.8Hz),123.4,53.4,53.0；HRMS(EI)Calcd.for C14H10F3NO4:[M+],313.0562.Found:m/z 313.0564.
Wherein, the chemical structure of general formula of preparing of described 2,4- diphenylquinoline is：
Embodiment 10
A kind of synthetic method of the preparation of 6- methoxyl group -4- phenylchinoline -2- Ethyl formate, comprises the following steps：
P-nethoxyaniline 1.0mmol (123.1mg), diethyl butyn ester is sequentially added in reaction vessel 1.1mmol (156.2mg), phenylpropiolic acid methyl esters 1.0mmol (160.2mg), catalyst Cu (OAc)20.005mmol (1.8mg), HOTf 0.01mmol (1.5mg), solvent nitrile 2mL, react 18h in 100 DEG C of oil baths, are cooled to room temperature, add water 5mL, is extracted with ethyl acetate three times, merges organic layer, reduced pressure concentration, product purifies through column chromatography, 300-400 mesh silica gel Post, eluant, eluent is the mixture of ethyl acetate and petroleum ether, and both volume ratios are 1:5, obtain white solid product 278.62mg, Yield 74%, purity 99.9%.1H NMR(400MHz,CDCl3) δ 8.29 (d, J=12.0Hz, 1H), 8.10 (s, 1H), 7.56- 7.50 (m, 5H), 7.45 (d, J=8.0Hz, 1H), 7.22 (s, 1H), 4.58-4.53 (q, J=8.0,12.0Hz, 2H), 3.81 (s, 3H), 1.49 (t, J=4.0Hz, 3H)；13C NMR(100MHz,CDCl3)δ165.6,159.5,148.0,145.4, 144.3,137.9,132.7,129.3,129.2,128.8,128.7,122.8,121.8,103.2,62.1,55.5,14.4； HRMS(EI)Calcd.for C19H17NO3:[M+],308.1279.Found:m/z 308.1279.
Wherein, the chemical structure of general formula of preparing of described 6- methoxyl group -4- phenylchinoline -2- Ethyl formate is：
The present invention has developed a kind of aniline of utilization TFMS copper catalysis substituent and electrophilic alkynes synthesis of quinoline The method of derivative, the method is applicable not only to the aniline of supplied for electronic replacement, also has preferable yield for electrophilic aniline. This method is a kind of novel method that is cheap, efficiently preparing substituted quinoline derivatives easy and simple to handle, safe.With prior art Compare, the method can be applied not only to substantial amounts of functional group, and simple to operate, yield be high, product is single, be easy to separate and Purification, safely cheap, pollution are little.

Claims (5)

1. a kind of synthetic method of quinoline -2 formic acid esters radical derivative, is characterized in that comprising the following steps：
In molar ratio 1 in reaction vessel：2～4 sequentially add aromatic amine I and electrophilic alkynes II, by 1mmol aromatic amine The ratio adding 2～4mL solvent adds solvent, is subsequently added into catalyst copper trifluoromethanesulfcomposite Cu (OTf)2, additive fluoroform Sulfonic acid HOTf, addition is respectively 0.8%～5%, the 1.8%～10% of aromatic amine mole, in 80 DEG C～120 DEG C oil baths Under the conditions of react 8～24h, be cooled to room temperature, add water, be extracted with ethyl acetate three times, merge organic layer, reduced pressure concentration, product Purify through column chromatography, obtain product quinoline, the reaction expression of its synthetic method is expressed as follows：
The quinoline chemical structure of general formula of synthesis is as follows：
Wherein, R1For-H, C1～C6Chain-like alkyl, C1～C6Chain alkoxyl ,-NO2,-OH, F ,-Br or Cl；R2For-H, C1~ C6Chain-like alkyl or phenyl.
2. the synthetic method of a kind of quinoline -2 formic acid esters radical derivative according to claim 1, is characterized in that described virtue Fragrant race amine I is aniline, adjacent fluoroaniline, m-fluoroaniline, para-fluoroaniline, o-chloraniline, m-chloroaniline, parachloroanilinum, o-bromoaniline, M-bromoaniline, para-bromoaniline, ortho-nitraniline, meta nitro aniline, paranitroanilinum, o-aminoanisole, m-anisidine, P-nethoxyaniline, o-toluidine, m-toluidine, open-chain crown ether, adjacent trifluoromethyl aniline, a trifluoromethyl aniline or to trifluoro Aniline.
3. the synthetic method of a kind of quinoline -2 formic acid esters radical derivative according to claim 1, is characterized in that described suction Electronics alkynes II is dimethyl butyn, diethyl butyn, phenylpropiolic acid methyl esters, ethyl phenylpropiolate, propiolic acid first Ester, tetrolic acid methyl esters, ethyl propiolate or ethyl butyn.
4. the synthetic method of a kind of quinoline -2 formic acid esters radical derivative according to claim 1, is characterized in that described molten Agent is toluene, methyl alcohol, nitrile, THF or 1,2- dichloroethanes.
5. the synthetic method of a kind of quinoline -2 formic acid esters radical derivative according to claim 1, is characterized in that described post Chromatography condition is：300～400 mesh silicagel columns, eluant, eluent is the mixture of ethyl acetate and petroleum ether, and both volume ratios are 1:10 ～1:5.
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