CN104860881A - Methods for synthesizing 8-(nitro methyl) quinoline compounds and 8-methylamino tetrahydroquinoline compounds - Google Patents

Methods for synthesizing 8-(nitro methyl) quinoline compounds and 8-methylamino tetrahydroquinoline compounds Download PDF

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CN104860881A
CN104860881A CN201510258069.9A CN201510258069A CN104860881A CN 104860881 A CN104860881 A CN 104860881A CN 201510258069 A CN201510258069 A CN 201510258069A CN 104860881 A CN104860881 A CN 104860881A
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formula
reaction
nitromethyla
nitration
toluquinoline
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刘运奎
张巍
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Zhejiang University of Technology ZJUT
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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
    • C07D215/12—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
    • C07D215/18—Halogen atoms or nitro radicals

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  • Organic Chemistry (AREA)
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Abstract

The invention provides a method for synthesizing 8-(nitro methyl) quinoline compounds. The method comprises steps as follows: 8-methylquinoline compounds are taken as raw materials and added to an organic solvent with a catalyst and a nitration reagent, the mixture is subjected to closed heating to the temperature of 80-130 DEG C for a reaction, TLC (thin layer chromatography) trace is performed until the reaction is finished, and the 8-(nitro methyl) quinoline compounds represented by the formula II are prepared through post-processing of a reaction liquid; the catalyst is bivalent palladium salt; the nitration reagent is tert-butyl nitrite. The 8-(nitro methyl) quinoline compounds can be further reduced for preparing 8-methylamino tetrahydroquinoline. The nitration method has the advantage of nitration position specificity, nitration is only performed on methyl, generation of nitration products on a benzene ring is avoided, the reaction process is safe and environment-friendly, the substrate adaptability is good, and methyl nitration of various substituent groups can be realized; 8-methylquinoline is directly taken as the raw material, the reaction steps are simple, and a new path for synthesizing various substituent group containing 8-(nitro methyl) quinoline compounds and further synthesizing 8-methylamino tetrahydroquinoline later is provided.

Description

The synthetic method of 8-(nitromethyla) quinolines and 8-methylamino-Tetrahydroquinolinesas
Technical field
The present invention relates to a kind of synthetic method of organic compound, relate in particular to the method for synthesizing 8-(nitromethyla) quinolines and then preparing 8-methylamino-tetrahydroquinoline.
Background technology
8-toluquinoline compounds and 8-methylamino-Tetrahydroquinolinesas are important industrial chemicals, main as medicine and organic synthesis intermediate, have a wide range of applications in medication chemistry industry.And in 8-toluquinoline methyl fragment, introduce nitro, this compounds can be made to have potential physiologically active, and the 8-aminomethyl quinoline also equally as pharmaceutical intermediate with physiologically active can be obtained thus.And the 8-toluquinoline containing different substituents is through the process of above-mentioned introducing nitro, expand the kind of this compounds, this compounds also can have been made to obtain and apply widely.Hydrogenated quinoline compounds is mainly used as medicine and organic synthesis intermediate, has a wide range of applications in medicine, chemical industry.At present also not about the report of the method for these two kinds of compounds of synthesis.Directly nitrated at present for alkyl, usually need the high temperature more than 200 DEG C, for the 8-toluquinoline containing heterocycle, under the condition more than 200 DEG C of high temperature, easily there is fracture open loop in self structure.And the industrial main introducing carrying out nitro with nitric acid and sulfuric acid mixed acid nitrification, for the 8-toluquinoline containing aromatic ring, nitro is easier to be incorporated on aromatic ring, causes that target product purity is low even can not get target product.Meanwhile, strong acid is easy and quinolines salify in reaction process, affects reaction and carries out, cause wastage of material, and release a large amount of heat in process, easily causes and produces danger, produce a large amount of waste gas spent acid simultaneously, cause serious environmental problem.
At present 8-(nitromethyla) quinoline and 8-methylamino-Tetrahydroquinolinesas are not also had to currently known methods to synthesize, and utilize existing nitrifying method to prepare and be difficult to obtain target product, and bring series of environmental problems and safety problem.
In view of above Problems existing, design one general, the synthetic route of simple 8-(nitromethyla) quinolines and 8-methylamino-tetrahydroquinoline seems and is extremely necessary.
Summary of the invention
For solving the problems that prior art exists in 8-(nitromethyla) quinolines building-up process, the present invention proposes the novel method of a kind of synthesis 8-(nitromethyla) quinolines and 8-methylamino-tetrahydroquinoline, the method is easy, efficiently.
The technical solution used in the present invention is:
The method of 8-(nitromethyla) quinolines shown in synthesis type II, described method for: with the 8-toluquinoline compounds shown in formula I for raw material, add in organic solvent with catalyzer and nitrating agent, under oxygen atmosphere, airtightly be heated to 80-130 DEG C of reaction, TLC tracks to after reaction terminates, and reaction solution aftertreatment obtains 8-(nitromethyla) quinolines shown in formula II;
In formula I or formula II, R 1, R 2, R 3, R 4, R 5, R 6respective is independently the aromatic base of hydrogen, the alkyl of C1 ~ C3, halogen, nitro or C6 ~ C12; Described halogen is fluorine, chlorine, bromine or iodine;
Preferred R 1, R 2, R 3, R 4, R 5, R 6respective is independently hydrogen, methyl, fluorine, chlorine, bromine, nitro or phenyl.
Further, preferred R 1for hydrogen; R 2for hydrogen or phenyl; R 3for hydrogen, R 4for hydrogen, methyl, fluorine, chlorine, bromine, nitro or phenyl; R 5for hydrogen, methyl, nitro or chlorine; R 6for hydrogen, fluorine or chlorine.
Described catalyzer is divalent palladium salt, preferred palladium chloride, Palladium Diacetate, diacetonitrile palladium chloride or trifluoracetic acid palladium, more preferably Palladium Diacetate;
Described nitrating agent is nitrite tert-butyl, and described nitrating agent is 1 ~ 4:1 with the ratio of the amount of substance of the 8-toluquinoline compounds shown in formula I, preferred 3:1.
Described catalyzer is 1:5 ~ 10 with the ratio of the amount of substance of the 8-toluquinoline compounds shown in formula I, is preferably 1:10.
Described organic solvent is low polar organic solvent, preferred acetonitrile, tetrahydrofuran (THF) or 1,2-ethylene dichloride, more preferably 1,2-ethylene dichloride.
Under described oxygen atmosphere, the pressure of preferred oxygen is a normal atmosphere.
The volumetric usage of described organic solvent generally counts 5 ~ 20mL/mmol, preferred 10mL/mmol with the amount of substance of the 8-toluquinoline compounds shown in formula I.
Described temperature of reaction is 80-130 DEG C, is preferably 90 DEG C.
The present invention's reaction judges to react completely end with TLC tracking monitor raw material reaction situation, and the General reactions time is 20-48 hour, is preferably 48 hours.
Described reaction solution post-treating method is, after reaction terminates, filter after reaction solution dchloromethane, filtrate is separated with column chromatography chromatogram, leacheate is the mixed solvent of sherwood oil, ethyl acetate volume ratio 10:1, collect the elutriant containing product, elutriant steams and desolventizes 8-(nitromethyla) quinolines shown in obtained formula II.
The present invention also provides the method preparing 8-methylamino-Tetrahydroquinolinesas, said method comprising the steps of:
(1) with the 8-toluquinoline compounds shown in formula I for raw material, add in organic solvent with catalyzer and nitrating agent, under oxygen atmosphere, airtightly be heated to 80-130 DEG C of reaction, TLC tracks to after reaction terminates, and reaction solution aftertreatment obtains 8-(nitromethyla) quinolines shown in formula II;
(2) under ice bath, 8-(nitromethyla) quinolines shown in formula II, six hydration Nickel Chlorides add in methanol solvate, slowly add sodium borohydride again, stirring reaction 30 ~ 60 minutes, reaction product obtains the 8-methylamino-Tetrahydroquinolinesas shown in formula III through aftertreatment.
In formula I, formula II or formula III, R 1, R 2, R 3, R 4, R 5, R 6respective is independently the aromatic base of hydrogen, the alkyl of C1 ~ C3, halogen, nitro or C6 ~ C12; Described halogen is fluorine, chlorine, bromine or iodine;
Preferred R 1, R 2, R 3, R 4, R 5, R 6be hydrogen.
In described step (2), 8-(nitromethyla) quinolines shown in described formula II is 10:1 with the ratio of the amount of substance of six hydration Nickel Chlorides, and the ratio of the amount of substance of 8-(nitromethyla) quinolines shown in described formula II, sodium borohydride is 1:20.
In described step (2), the volumetric usage of described methyl alcohol generally counts 5 ~ 20mL/mmol, preferred 10mL/mmol with the amount of substance of 8-(nitromethyla) quinolines shown in formula II.
In described step (2), described reaction product post-treating method is: after reaction terminates, reaction product is filtered, filtrate is separated with column chromatography chromatogram, leacheate is the mixed solvent of sherwood oil, ethyl acetate volume ratio 6:1, collect the elutriant containing product, elutriant steams and desolventizes the 8-methylamino-Tetrahydroquinolinesas shown in obtained formula III.
The present invention directly with 8-toluquinoline (can various substituting group be contained) for raw material, be catalyzer at palladium, when nitrating agent and oxygen atmosphere exist, 8-toluquinoline methyl position there is mono-nitration reaction, obtain a series of 8-(nitromethyla) quinolines and then 8-methylamino-tetrahydroquinoline can be synthesized.
Compared with prior art, the invention has the beneficial effects as follows:
(1) safety and environmental protection, does not produce waste gas waste water;
(2) substrate adaptability is good, and various substituting group can realize nitrated;
(3) nitration reaction regioselectivity is good;
(4) reactions steps is simple, and is the various variation route containing substituent 8-(nitromethyla) quinolines of a kind of synthesis;
Embodiment
Below by embodiment, the present invention is described in further detail, but protection scope of the present invention is not limited thereto.
Embodiment 1:
(1) under an atmospheric oxygen atmosphere by 8-toluquinoline 0.5mmol (71.5mg), Palladium Diacetate 0.05mmol (11.2mg), nitrite tert-butyl 1.5mmol (154.5mg) and 1,2-ethylene dichloride 5ml adds in the sealed pressure vessel of 25ml volume successively.By mixture reacting by heating 48 hours in 90 DEG C of oil baths.After TLC detection reaction terminates, reaction solution dchloromethane, filtration obtains clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains 8-(nitromethyla) quinoline (93% yield).
White solid; M.p.64-65 DEG C; IR (KBr): ν=1518 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 8.98 (dd, J 1=4.5, J 2=2.0Hz, 1H), 8.20 (dd, J 1=8.5, J 2=2.0Hz, 1H), 7.89 (dd, J 1=8.5Hz, J 2=1.0Hz, 1H), 7.81 (d, J=7.0Hz, 1H), 7.57 (t, J=8.5Hz, 1H), 7.48 (dd, J 1=8.0Hz, J 2=4.5Hz, 1H), 6.22 (s, 2H); 13c NMR (CDCl 3, 125MHz): δ 150.3,146.2,136.3,130.6,129.9,129.5,128.3,126.1,121.7,71.1;
Then under ice bath by 1mmol 8-(nitromethyla) quinoline, 0.1mmol six hydration Nickel Chloride in molar ratio 10:1 ratio adds in 10mL methyl alcohol, the sodium borohydride slowly adding 20mmol again stirs 30 minutes, reaction terminates rear filtration, obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 6:1), collect the elutriant containing product, elutriant steams to desolventize and obtains 8-methylamino-tetrahydroquinoline (92% yield).
Yellow liquid; IR (neat): ν=3396 (NH) cm -1; 1h NMR (CDCl 3, 500MHz): δ 6.96 (d, J=7.5Hz, 1H), 6.91 (d, J=7.5Hz, 1H), 6.58 (t, J=7.5Hz, 1H), 4.83 (s, 2H), 3.38 (t, J=5.5Hz, 2H), 3.15 (br s, 3H), 2.81 (t, J=6.0Hz, 2H), 1.98 – 1.93 (m, 2H); 13c NMR (CDCl 3, 125MHz): δ 143.9,129.7,126.9,123.7,122.0,116.0,64.5,42.0,27.3,21.8;
Embodiment 2:
By 8-methyl-3-phenylquinoline 0.5mmol under oxygen atmosphere, Palladium Diacetate 0.06mmol, nitrite tert-butyl 1.0mmol and 1,2-ethylene dichloride 5ml add in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 30 hours in 90 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains 8-(nitromethyla) 3-phenylquinoline (64% yield).
Yellow liquid; IR (neat): ν=1518 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 9.24 (d, J=2.5Hz, 1H), 8.34 (d, J=2.5Hz, 1H), 7.95 (dd, J 1=7.5Hz, J 2=1.5Hz, 1H), 7.80 – 7.48 (m, 8H), 6.25 (s, 2H); 13c NMR (CDCl 3, 125 MHz): δ 149.8,145.1,138.5,137.5,134.5,133.4,130.5,129.8,129.6,129.3,128.3,127.4,126.6,71.1;
Embodiment 3:
By 5,8-dimethyl-3-phenylquinoline 0.5mmol under oxygen atmosphere, Palladium Diacetate 0.05mmol, nitrite tert-butyl 1.5mmol and 1,2-ethylene dichloride 3ml add in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 48 hours in 100 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains 5-methyl-8-(nitromethyla) 3-phenylquinoline (81% yield).
Yellow liquid IR (neat): ν=1517 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 9.26 (d, J=2.0Hz, 1H), 8.52 (s, 1H), 7.74 – 7.72 (m, 3H), 7.59 – 7.45 (m, 5H), 6.22 (s, 2H), 2.79 (s, 3H); 13c NMR (CDCl 3, 125MHz): δ 149.1,137.0,134.2,129.3,128.4,127.9,127.6,127.5,127.2,71.4,18.9;
Embodiment 4:
By chloro-for 6-8-methyl 3-phenylquinoline 0.5mmol under oxygen atmosphere, trifluoracetic acid palladium 0.06mmol, nitrite tert-butyl 1.5mmol and 1,2-ethylene dichloride 3ml add in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 48 hours in 80 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains the chloro-8-of 6-(nitromethyla) 3-phenylquinoline (50% yield).
Yellow liquid, IR (neat): ν=1518 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 9.21 (d, J=2.0Hz, 1H), 8.23 (d, J=2.5Hz, 1H), 7.90 (d, J=2.0Hz, 1H), 7.74 – 7.47 (m, 6H), 6.20 (s, 2H); 13c NMR (CDCl 3, 125MHz): δ 150.0,143.4,137.1,135.4,132.3,129.9,129.3,128.6,127.8,127.4,70.1;
Embodiment 5:
Under oxygen atmosphere, 5,8-dimethyl quinoline 0.5mmol, palladium chloride 0.05mmol, nitrite tert-butyl 1.5mmol and 1,2-ethylene dichloride 5ml are added in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 48 hours in 1100 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains 5-methyl-8-(nitromethyla) quinoline (43% yield).
White solid, m.p.82-84 DEG C; IR (neat): ν=1515 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 8.98 (dd, J 1=4.5Hz, J 2=1.5Hz, 1H), 8.38 (dd, J 1=8.5Hz, J 2=2.0Hz, 1H), 7.70 (d, J=9.0Hz, 1H), 7.50 (dd, J 1=8.5Hz, J 2=4.0Hz, 1H), 7.40 (d, J=7.0Hz, 1H), 6.17 (s, 2H), 2.72 (s, 3H); 13cNMR (CDCl 3, 125MHz): δ 149.8,146.3,136.8,132.9,130.2,128.4,127.7,126.6,121.2,71.5,18.7;
Embodiment 6:
By fluoro-for 5-8-toluquinoline 0.5mmol under oxygen atmosphere, diacetonitrile palladium chloride 0.05mmol, nitrite tert-butyl 1.5mmol and 1,2-ethylene dichloride 5ml add in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 48 hours in 120 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains 5 fluoro-8-(nitromethyla) quinoline (63% yield).
White solid; M.p.51-53 DEG C; IR (KBr): ν=1519 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 9.02 (dd, J 1=4.5Hz, J 2=1.5Hz, 1H), 8.47 (dd, J 1=8.5Hz, J 2=2.0Hz, 1H), 7.77 (dd, J 1=7.5Hz, J 2=2.0Hz, 1H), 7.54 (dd, J 1=8.5Hz, J 2=4.0Hz, 1H), 7.24 (dd, J 1=8.0Hz, J 2=1.5Hz, 1H), 6.15 (s, 2H); 13c NMR (CDCl 3, 125MHz): δ 158.6 (d, J=257.5Hz), 151.2,146.9 (d, J=2.5Hz), 130.2 (d, J=10Hz), 129.5 (d, J=5Hz), 126.7 (d, J=3.8Hz), 121.7 (d, J=2.5Hz), 119.2 (d, J=16.3Hz), (109.7 d, J=20Hz), 70.7;
Embodiment 7:
By 6,8-dimethyl quinoline 0.5mmol under oxygen atmosphere, trifluoracetic acid palladium 0.05mmol, nitrite tert-butyl 2mmol and 1,2-ethylene dichloride 5ml add in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 30 hours in 80 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains 6-methyl 8-(nitromethyla) quinoline (61% yield).
White solid; M.p.62-64 DEG C; IR (KBr): ν=1517 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 8.90 (d, J=2.5Hz, 1H), 8.11 (dd, J 1=8.0Hz, J 2=1.5Hz, 1H), 7.64 (s, 2H), 7.44 (dd, J 1=8.0Hz, J 2=4.0Hz, 1H), 6.18 (s, 2H), 2.56 (s, 3H); 13c NMR (CDCl 3, 125MHz): δ 149.5,144.8,136.1,135.6,132.2,130.2,128.4,128.2,71.2,21.6;
Embodiment 8:
Under oxygen atmosphere, chloro-for 5-8-toluquinoline 0.5mmol, Palladium Diacetate 0.05mmol, nitrite tert-butyl 2mmol and 1,2-ethylene dichloride 4ml are added in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 48 hours in 90 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains the chloro-8-of 5-(nitromethyla) quinoline (83% yield).
White solid, m.p.49-51 DEG C; IR (KBr): ν=1519 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 9.00 (dd, J 1=4.0Hz, J 2=1.5Hz, 1H), 8.60 (dd, J 1=8.5Hz, J 2=2.0Hz, 1H), 7.72 (d, J=7.5Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.58 (t, J=4.0Hz, 1H), 6.16 (s, 2H); 13c NMR (CDCl 3, 125MHz): δ 150.9,146.6,133.1,132.9,130.1,129.5,126.4,126.2,122.4,70.7
Embodiment 9
Under oxygen atmosphere, chloro-for 7-8-toluquinoline 0.5mmol, Palladium Diacetate 0.05mmol, nitrite tert-butyl 1.5mmol and acetonitrile 5ml are added in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 36 hours in 110 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains the chloro-8-of 7-(nitromethyla) quinoline (70% yield).
White solid, m.p.106-108 DEG C; IR (KBr): ν=1520 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 8.99 (dd, J 1=4.0Hz, J 2=1.5Hz, 1H), 8.18 (d, J=8.0Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 7.60 (d, J=8.0Hz, 1H), 7.48 (dd, J 1=8.5Hz, J 2=4.5Hz, 1H), 6.39 (s, 2H); 13c NMR (CDCl 3, 125MHz): δ 151.4,147.4,138.0,136.2,128.1,127.2,126.8,121.7,67.6;
Embodiment 10
By bromo-for 5-8-toluquinoline 0.5mmol under oxygen atmosphere, trifluoracetic acid palladium 0.05mmol, nitrite tert-butyl 2.5mmol and 1,2-ethylene dichloride 5ml add in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 24 hours in 100 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains the bromo-8-of 5-(nitromethyla) quinoline (56% yield).
White solid, m.p.47-48 DEG C; IR (KBr): ν=1520 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 8.99 (dd, J 1=4.5Hz, J 2=1.5Hz, 1H), 8.59 (dd, J 1=8.5Hz, J 2=1.5Hz, 1H), 7.87 (d, J=8.0Hz, 1H), 7.67 (d, J=8.0Hz, 1H), 7.59 (t, J=4.5Hz, 1H), 6.17 (s, 1H); 13c NMR (CDCl 3, 125MHz): δ 151.0,146.7,135.9,130.9,130.0,129.9,127.8,123.6,122.8,70.7;
Embodiment 11:
By 6-nitro 8-toluquinoline 0.5mmol under oxygen atmosphere, Palladium Diacetate 0.06mmol, nitrite tert-butyl 2mmol and 1,2-ethylene dichloride 3ml add in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 48 hours in 100 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains 6-nitro-8-(nitromethyla) quinoline (66% yield).
White solid; M.p.105-107 DEG C; IR (KBr): ν=1523 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 9.14 (dd, J 1=4.5Hz, J 2=2.0Hz, 1H), 8.84 (d, J=2.5Hz, 1H), 8.56 (d, J=2.5Hz, 1H), 8.42 (dd, J 1=8.5Hz, J 2=1.5Hz, 1H), 7.67 (dd, J 1=8.5Hz, J 2=4.5Hz, 1H), 6.24 (s, 2H); 13c NMR (CDCl 3, 125MHz): δ 153.6,147.8,145.0,138.2,133.7,127.2,125.5,123.5,122.4,69.8;
Embodiment 12
By 5-nitro-8-toluquinoline 0.5mmol under oxygen atmosphere, Palladium Diacetate 0.05mmol, nitrite tert-butyl 3mmol and 1,2-ethylene dichloride 5ml add in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 48 hours in 80 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains 5-nitro 8-(nitromethyla) quinoline (59% yield).
White solid, m.p.68-70 DEG C; IR (KBr): ν=1519 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 9.08 – 9.04 (m, 2H), 8.40 (d, J=8.0Hz, 1H), 7.88 (d, J=8.0Hz, 1H), 7.73 (dd, J 1=9.0Hz, J 2=4.5Hz, 1H), 6.28 (s, 1H); 13c NMR (CDCl 3, 125MHz): δ 151.2,145.9,145.6,138.7,132.4,126.2,124.4,124.1,121.3,70.2;
Embodiment 13
By 5-phenyl-8-toluquinoline 0.5mmol under oxygen atmosphere, palladium chloride 0.05mmol, nitrite tert-butyl 1.5mmol and 1,2-ethylene dichloride 5ml add in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 48 hours in 90 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains 8-(nitromethyla)-5-phenylquinoline (53% yield).
White solid, m.p.88-90 DEG C; IR (KBr): ν=1518 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 8.97 (dd, J 1=4.0Hz, J 2=1.5Hz, 1H), 8.24 (d, J=1.5Hz, 1H), 8.06 (dd, J 1=9.5Hz, J 2=2.0Hz, 1H), 7.72 (dd, J 1=8.0Hz, J 2=1.0Hz, 1H), 7.54 – 7.45 (m, 4H), 6.27 (s, 2H); 13c NMR (CDCl 3, 125MHz): δ 150.2,145.5,139.8,139.1,136.5,131.2,129.7,129.1,128.6,128.1,127.5,126.9,122.0,71.1;
Embodiment 14:
Under oxygen atmosphere, fluoro-for 7-8-toluquinoline 0.5mmol, Palladous chloride 0.05mmol, nitrite tert-butyl 2mmol and 1,2-ethylene dichloride 5ml are added in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 48 hours in 90 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains the fluoro-8-of 7-(nitromethyla) quinoline (55% yield).
White solid, m.p.86-88 DEG C; IR (KBr): ν=1524 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 9.00 (dd, J 1=4.0Hz, J 2=1.5Hz, 1H), 8.20 (dd, J 1=8.5Hz, J 2=2.0Hz, 1H), 7.93 (dd, J 1=9.0Hz, J 2=6.0Hz, 1H), 7.48 – 7.39 (m, 2H), 6.24 (d, J=1.5Hz, 2H); 13c NMR (CDCl 3, 125 MHz): δ 162.3 (d, J=253.8Hz), 151.5,147.4 (d, J=7.5Hz), 136.3,131.9 (d, J=10Hz), 125.3,121.0,116.8 (d, J=25Hz), 114.5 (d, J=13.8Hz), 64.2;
Embodiment 15:
Under oxygen atmosphere, chloro-for 6-8-toluquinoline 0.5mmol, Palladous chloride 0.05mmol, nitrite tert-butyl 1.5mmol and acetonitrile 5ml are added in the sealed pressure vessel of 25ml successively.By mixture reacting by heating 48 hours in 120 DEG C of oil baths.After TLC detection reaction terminates, filter after reaction solution dchloromethane and obtain clear liquid, be separated by column chromatography chromatogram method (leacheate proportioning: sherwood oil is to ethyl acetate volume ratio 10:1), collect the elutriant containing product, elutriant steams to desolventize and obtains the chloro-8-of 6-(nitromethyla) quinoline (62% yield).
White solid; M.p.52-54 DEG C; IR (KBr): ν=1520 (NO 2) cm -1; 1h NMR (CDCl 3, 500MHz): δ 8.95 (dd, J 1=4.0Hz, J 2=1.5Hz, 1H), 8.13 (dd, J 1=8.5Hz, J 2=1.5Hz, 1H), 7.86 (d, J=2.5Hz, 1H), 7.75 (d, J=2.5Hz, 1H), 7.51 (dd, J 1=8.0Hz, J 2=4.0Hz, 1H), 6.18 (s, 2H); 13c NMR (CDCl 3, 125MHz): δ 150.4,144.5,135.4,133.1,132.0,130.1,129.0,127.7,122.5,70.1.

Claims (10)

1. the method for 8-(nitromethyla) quinolines shown in synthesis type II, is characterized in that described method is:
With the 8-toluquinoline compounds shown in formula I for raw material, add in organic solvent with catalyzer and nitrating agent, under oxygen atmosphere, airtightly be heated to 80-130 DEG C of reaction, TLC tracks to after reaction terminates, and reaction solution aftertreatment obtains 8-(nitromethyla) quinolines shown in formula II;
In formula I or formula II, R 1, R 2, R 3, R 4, R 5, R 6respective is independently the aromatic base of hydrogen, the alkyl of C1 ~ C3, halogen, nitro or C6 ~ C12; Described halogen is fluorine, chlorine, bromine or iodine;
Described catalyzer is divalent palladium salt; Described nitrating agent is nitrite tert-butyl.
2. the method for claim 1, is characterized in that described R 1, R 2, R 3, R 4, R 5, R 6respective is independently hydrogen, methyl, fluorine, chlorine, bromine, nitro or phenyl.
3. the method for claim 1, is characterized in that described catalyzer is palladium chloride, Palladium Diacetate, diacetonitrile palladium chloride or trifluoracetic acid palladium.
4. the method for claim 1, is characterized in that described catalyzer is 1:5 ~ 10 with the ratio of the amount of substance of the 8-toluquinoline compounds shown in formula I.
5. the method for claim 1, its feature is 1 ~ 4:1 at described nitrating agent and the ratio of the amount of substance of the 8-toluquinoline compounds shown in formula I.
6. the method for claim 1, is characterized in that described organic solvent is acetonitrile, tetrahydrofuran (THF) or 1,2-ethylene dichloride.
7. the method for claim 1, is characterized in that the volumetric usage of described organic solvent counts 5 ~ 20mL/mmol with the amount of substance of the 8-toluquinoline compounds shown in formula I.
8. the method for claim 1, it is characterized in that described reaction solution post-treating method is, after reaction terminates, filter after reaction solution dchloromethane, filtrate is separated with column chromatography chromatogram, leacheate is the mixed solvent of sherwood oil, ethyl acetate volume ratio 10:1, collects the elutriant containing product, and elutriant steams and desolventizes 8-(nitromethyla) quinolines shown in obtained formula II.
9. synthesize the method for the 8-methylamino-Tetrahydroquinolinesas shown in formula III, it is characterized in that said method comprising the steps of:
(1) with the 8-toluquinoline compounds shown in formula I for raw material, add in organic solvent with catalyzer and nitrating agent, under oxygen atmosphere, airtightly be heated to 80-130 DEG C of reaction, TLC tracks to after reaction terminates, and reaction solution aftertreatment obtains 8-(nitromethyla) quinolines shown in formula II;
(2) under ice bath, 8-(nitromethyla) quinolines shown in formula II, six hydration Nickel Chlorides add in methanol solvate, slowly add sodium borohydride again, stirring reaction 30 ~ 60 minutes, reaction product obtains the 8-methylamino-Tetrahydroquinolinesas shown in formula III through aftertreatment;
In formula I, formula II or formula III, R 1, R 2, R 3, R 4, R 5, R 6respective is independently the aromatic base of hydrogen, the alkyl of C1 ~ C3, halogen, nitro or C6 ~ C12; Described halogen is fluorine, chlorine, bromine or iodine;
In described step (1), described catalyzer is divalent palladium salt; Described nitrating agent is nitrite tert-butyl.
10. method as claimed in claim 9, it is characterized in that in described step (2), 8-(nitromethyla) quinolines shown in described formula II is 10:1 with the ratio of the amount of substance of six hydration Nickel Chlorides, and the ratio of the amount of substance of 8-(nitromethyla) quinolines shown in described formula II, sodium borohydride is 1:20.
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