CN108558750A - The technique that solventless method synthesizes 3- nitroquinoline derivatives - Google Patents
The technique that solventless method synthesizes 3- nitroquinoline derivatives Download PDFInfo
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- CN108558750A CN108558750A CN201810758186.5A CN201810758186A CN108558750A CN 108558750 A CN108558750 A CN 108558750A CN 201810758186 A CN201810758186 A CN 201810758186A CN 108558750 A CN108558750 A CN 108558750A
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- aryl
- nitroolefin
- ortho position
- substitution
- aldehyde radical
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- XAWUADQAXGATHK-UHFFFAOYSA-N CC1[N](C)(C)CC1 Chemical compound CC1[N](C)(C)CC1 XAWUADQAXGATHK-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to a kind of methods that 3 nitroquinolines are synthesized under solvent-free system：Under solvent-free conditions, [3+2] cycloaddition reaction occurs under the action of copper salt catalyst for nitroolefin and the aryl azide of ortho position aldehyde radical substitution, wherein nitroolefin be alkyl, substitution alkyl, aryl or substituted aryl nitroolefin, ortho position aldehyde radical substitution aryl azide in aryl be aryl or substituted aryl.The beneficial effects of the invention are as follows：The present invention uses the aryl azide and nitroolefin of ortho position aldehyde radical substitution, and in the absence of a solvent, using mantoquita as catalyst, high yield obtains 3 nitroquinoline compounds.Raw material is simple and easy to get, and byproduct of reaction only has nitrogen and water, and atom utilization is high, and solvent-free strategy greatly accelerates the reaction time, reduces the by-product that 2 nitrine benzaldehydes and solvent generate, post-processing is easy, environmentally friendly.
Description
Technical field
The present invention relates to a kind of methods that 3- nitroquinolines are synthesized under solvent-free system, belong to organic and medicine synthesis technique
Field.
Technical background
Quinoline is a kind of important nitrogen-containing heterocycle compound in organic synthesis.Wherein, the quinoline of No. 3 position nitrogen-atoms substitutions
It is widely present in natural products, such as cryptolepine Alkaloid, the activity with good anti-malarial and anticancer, in addition, one
The compound for containing this skeleton a bit also has anticancer, antimalarial, anti-asthma, anti-diabetic, antibacterial, the characteristics such as antitumor.3- nitre
The characteristics of there is property to stablize, be easy to derivatization for precursor of the base quinolines as this kind of compound, in organic synthesis
It is concerned, there is sizable potential quality on pharmaceutical synthesis.
However up to the present, the method for 3- nitroquinolines compound synthesis is considerably less, mainly there is following three kinds：(1)
Directly quinoline ring is nitrified, exist selectivity it is not high, generate the isomers of several positions, and quinoline ring, shape can be aoxidized
At the nitrogen oxides of quinoline, therefore the mode directly nitrified is rarely used in synthesis 3- nitroquinolines compounds.(2) 2- ammonia is used
Benzaldehyde and α-nitro ketone compounds are condensed to yield 3- nitroquinolines in alcohols solvent, but this ketone compounds exist
Relatively complicated in preparation, substrate has very strong limitation.(3) 2004 years, Yao Qing sent out seminar's report o-Aminobenzaldehyde and nitre
Base alkene is under conditions of DABCO is as organic base, using benzene as solvent refluxing, can obtain 3- nitro -1,2- dihydro quinolines
Quinoline, then oxidation obtains 3- nitroquinolines under the conditions of DDQ or silica gel.This method is widely adopted, but there are three aspects
Problem, first, needing to use the benzene being more toxic as solvent during first step cycloaddition, second is that due to o-Aminobenzaldehyde
It is very easy to polymerization, the price is very expensive, and yield can be caused to be lower in practice, third, reaction needs to be carried out in two steps, and
Use the alkali and oxidant of equivalent, post-processing complicated.
Invention content
To solve the deficiencies in the prior art, the present invention uses the aryl azide of ortho position aldehyde radical substitution cheap and easy to get for original
Material, 3- nitroquinolines compounds are obtained with nitroolefin under the catalysis of mantoquita, and solvent-free strategy greatly improves anti-
Answer rate.Byproduct of reaction only has nitrogen and water, and post-processing is simple, is a kind of environmental-friendly synthetic method.
In order to achieve the above objectives, the present invention is achieved by the following technical solutions：Solventless method synthesizes 3- nitros
The technique of quinoline, it is characterised in that：Under solvent-free conditions, nitroolefin and the aryl azide of ortho position aldehyde radical substitution exist
[3+2] cycloaddition reaction occurs under the action of copper salt catalyst, wherein nitroolefin is alkyl, substitution alkyl, aryl or substitution
The nitroolefin of aryl, ortho position aldehyde radical substitution aryl azide in aryl be aryl or substituted aryl.
Its specific reaction equation is as shown in formula I：
Ar is that either substituted aryl alkyl or substitution alkyl, R are halogen, methyl, methoxyl group, hydrogen or virtue to aryl in formula I
Base.
By said program, the copper salt catalyst is selected from CuI, CuCl, CuBr, Cu2O or Cu (OTf)2。
By said program, the copper salt catalyst is CuI.
By said program, the copper salt catalyst dosage is calculated as the 0.01-0.2 of nitroolefin dosage by the amount of substance
Times.
By said program, the copper salt catalyst dosage is calculated as 0.01 times of nitroolefin dosage by the amount of substance.
By said program, reaction carries out within the temperature range of 80-130 DEG C.
By said program, reaction carries out under the conditions of 110 DEG C.
By said program, the aryl azide of ortho position aldehyde radical substitution is calculated as 1-5 times of nitroolefin dosage by the amount of substance.
By said program, the aryl azide of ortho position aldehyde radical substitution is calculated as 1.5-2 times of nitroolefin dosage by the amount of substance.
By said program, the reaction time is 2-8 hours.
Using CuI as catalyst, under 110 DEG C of reaction conditions, specific reaction equation is：
Specifically reaction step is：By nitroolefin, the aryl azide of ortho position aldehyde radical substitution, after CuI mixing, in fire-bar
2-8 hour is reacted through magnetic agitation under part, after the completion of reaction, after being dissolved with ethyl acetate, organic layer is washed through saturated common salt
It washs, after anhydrous sodium sulfate drying, decompression boils off extractant up to crude product, is purified up to product 3- using column chromatography for separation
Nitroquinoline compound.
The beneficial effects of the invention are as follows：The present invention uses the aryl azide and nitroolefin of ortho position aldehyde radical substitution, without molten
Under conditions of agent, using mantoquita as catalyst, high yield obtains 3- nitroquinoline compounds.Raw material is simple and easy to get, and reaction is secondary
Product only has nitrogen and water, and atom utilization is high, and solvent-free strategy greatly accelerates the reaction time, reduces 2- nitrine
The by-product that benzaldehyde and solvent generate, post-processing is easy, environmentally friendly, is a kind of synthesis 3- with potential using value
The new method of nitroquinoline derivative.
Description of the drawings
In order to illustrate more clearly of the technical solution of case study on implementation of the present invention, is below made to the attached drawing of embodiment simple be situated between
It continues.
Fig. 1 is the 2- phenyl -3- nitroquinoline compounds that the embodiment of the present invention 1 synthesizes1H NMR characterize collection of illustrative plates；
Fig. 2 is the 2- phenyl -3- nitroquinoline compounds that the embodiment of the present invention 1 synthesizes13C NMR characterize collection of illustrative plates；
Fig. 3 is 2- (2- bromophenyls) -3- nitroquinoline compounds that the embodiment of the present invention 2 synthesizes1H NMR phenograms
Spectrum；
Fig. 4 is 2- (2- bromophenyls) -3- nitroquinoline compounds that the embodiment of the present invention 2 synthesizes13C NMR phenograms
Spectrum；
Fig. 5 is the 2- phenyl -3- nitro -7- fluorine quinoline compounds that the embodiment of the present invention 3 synthesizes1H NMR characterize collection of illustrative plates；
Fig. 6 is the 2- phenyl -3- nitro -7- fluorine quinoline compounds that the embodiment of the present invention 3 synthesizes13C NMR characterize collection of illustrative plates；
Fig. 7 is 2- (2- furyls) -3- nitroquinoline compounds that the embodiment of the present invention 4 synthesizes1H NMR phenograms
Spectrum；
Fig. 8 is 2- (2- furyls) -3- nitroquinoline compounds that the embodiment of the present invention 4 synthesizes13C NMR phenograms
Spectrum；
Fig. 9 is 2- phenyl -3- nitro -6,7- dimethoxy-quinoline compounds that the embodiment of the present invention 5 synthesizes1H NMR
Characterize collection of illustrative plates；
Figure 10 is 2- phenyl -3- nitro -6,7- dimethoxy-quinoline compounds that the embodiment of the present invention 5 synthesizes13C NMR
Characterize collection of illustrative plates.
Specific implementation mode
For a better understanding of the present invention, with reference to the embodiment content that the present invention is furture elucidated, but the present invention
Content is not limited solely to the following examples.
Embodiment 1：
The specific steps are：To addition nitrostyrolene (1mmol), 2- nitrine benzaldehydes in round-bottomed flask (50mL)
(1.5mmol), CuI (0.01mmol), after magnetic agitation is reacted 2 hours at 110 DEG C, after being dissolved with ethyl acetate, organic layer
Through saturated common salt water washing, after anhydrous sodium sulfate drying, decompression boils off extractant up to crude product, crude product acetic acid second
Ester/petroleum ether=1:10 (V/V) are that leacheate progress post separation purifies up to product 2- phenyl -3- nitroquinolines, solid for yellow
Body, yield 90%.
As the nucleus magnetic hydrogen spectrum figure result of Fig. 1 and Fig. 2, products obtained therefrom are：1H NMR(600MHz,DMSO-d6):δ8.60(s,
1H), 8.20 (d, J=8.4Hz, 1H), 7.90 (d, J=8.4Hz, 1H), 7.86 (t, J=7.8Hz, 1H), 7.63 (t, J=
7.2Hz, 1H), 7.58 (d, J=7.8Hz, 2H), 7.30 (d, J=7.8Hz, 2H), 2.42 (s, 3H)13C NMR(100MHz,
CDCl3,ppm)δ152.1,148.3,143.9,137.0,132.8,132.6,129.8,129.6,128.7,128.6,128.4,
128.1,125.5.
Embodiment 2：
The specific steps are：To addition nitro bromophenyl ethylene (1mmol), 2- nitrine benzaldehydes in round-bottomed flask (50mL)
(2mmol), CuI (0.01mmol), after magnetic agitation is reacted 3 hours at 110 DEG C, after being dissolved with ethyl acetate, organic layer warp
Saturated common salt water washing, after anhydrous sodium sulfate drying, decompression boils off extractant up to crude product, crude product with ethyl acetate/
Petroleum ether=1:10 (V/V) are that leacheate progress post separation purifies up to product 2- (2- bromophenyls) -3- nitroquinolines, are yellow
Solid, yield 88%.
As the nucleus magnetic hydrogen spectrum figure result of Fig. 3 and Fig. 4, products obtained therefrom are：1H NMR(600MHz,CDCl3,ppm)δ8.98(s,
1H), 8.25 (d, J=8.4Hz, 1H), 8.06 (d, J=7.8Hz, 1H), 7.95 (t, J=7.2Hz, 1H), 7.74 (t, J=
7.2Hz, 1H), 7.65 (d, J=7.8Hz, 1H), 7.59-7.45 (m, 2H), 7.34 (t, J=7.2Hz, 1H)13C NMR
(100MHz,CDCl3,ppm)δ152.2,148.5,143.0,139.4,133.4,133.3,132.4,130.3,130.1,
129.8,129.0,128.9,127.7,126.0,121.8.
Embodiment 3：
The specific steps are：To addition nitrostyrolene (1mmol), 2- nitrine -4- fluorobenzaldehydes in round-bottomed flask (50mL)
(1.5mmol)、Cu2O (0.01mmol), after magnetic agitation is reacted 4 hours at 110 DEG C, after being dissolved with ethyl acetate, organic layer
Through saturated common salt water washing, after anhydrous sodium sulfate drying, decompression boils off extractant up to crude product, crude product acetic acid second
Ester/petroleum ether=1:15 (V/V) are that leacheate progress post separation purifies up to product 2- phenyl -3- nitro -7- fluorine quinoline, product
For yellow solid, yield 85%.
As the nucleus magnetic hydrogen spectrum figure result of Fig. 5 and Fig. 6, products obtained therefrom are：1H NMR(600MHz,CDCl3,ppm)δ8.70(s,
1H), 8.03-7.97 (m, 1H), 7.86 (d, J=9.6Hz, 1H), 7.65 (s, 2H), 7.48-7.51 (m, 4H)13C NMR
(150MHz,CDCl3, ppm) and δ 166.0,164.3,153.3,149.6 (d, J=13.4Hz), 143.5,136.7,132.7,
130.8 (d, J=10.4Hz), 129.8,128.8,122.5,119.3 (d, J=25.9Hz), 113.8 (d, J=21.0Hz)
Embodiment 4：
The specific steps are：To addition 2- furans nitrostyrolene (1mmol), 2- nitrine benzaldehydes in round-bottomed flask (50mL)
(1.5mmol), CuCl (0.01mmol), after magnetic agitation is reacted 3 hours at 130 DEG C, after being dissolved with ethyl acetate, organic layer
Through saturated common salt water washing, after anhydrous sodium sulfate drying, decompression boils off extractant up to crude product, crude product acetic acid second
Ester/petroleum ether=1:15 (V/V) are that leacheate progress post separation purifies up to product 2- (2- furyls) -3- nitroquinolines, production
Product are yellow solid, yield 75%.
As the nucleus magnetic hydrogen spectrum figure result of Fig. 7 and Fig. 8, products obtained therefrom are：1H NMR(400MHz,CDCl3,ppm)δ8.45(s,
1H), 8.16 (d, J=8.4Hz, 1H), 7.83-7.89 (m, 2H), 7.65-7.60 (m, 2H), 7.23 (d, J=3.6Hz, 1H),
6.59-6.60(m,1H).13C NMR(100MHz,CDCl3,ppm)δ149.7,148.1,145.2,142.3,140.6,132.6,
131.7,129.6,128.4,128.4,125.3,113.1,112.3.
Embodiment 5：
The specific steps are：To addition nitrostyrolene (1mmol), 2- nitrine -4,5- dimethoxies in round-bottomed flask (50mL)
Benzaldehyde (1.8mmol), CuBr (0.01mmol) are dissolved after magnetic agitation is reacted 4 hours at 100 DEG C with ethyl acetate
Afterwards, organic layer is through saturated common salt water washing, and after anhydrous sodium sulfate drying, decompression boils off extractant up to crude product, crude product
With ethyl acetate/petroleum ether=1:2.5 (V/V) are that leacheate progress post separation purifies up to product 2- phenyl -3- nitros -6,7-
Dimethoxy-quinoline, product are yellow solid, yield 73%.
As the nucleus magnetic hydrogen spectrum figure result of Fig. 9 and Figure 10, products obtained therefrom are：1H NMR(600MHz,CDCl3,ppm)δ8.55
(s, 1H), 7.60 (d, J=4.8Hz, 2H), 7.52-7.44 (m, 4H), 7.15 (s, 1H), 4.05 (s, 3H), 4.04 (s, 3H)
.13C NMR(100MHz,CDCl3,ppm)δ155.3,151.4,150.3,146.1,142.5,137.6,130.9,129.1,
128.6,128.0,121.4,108.1,105.2,56.5,56.3.
The present invention, as catalyst, carries out the reaction of nitroolefin and 2- nitrine benzaldehydes using CuI cheap and easy to get
Catalysis, and solvent-free strategy is used, the progress of reaction has been significantly speeded up, the quinolate of 3- nitros substitution has been efficiently synthesized
Object is closed, compared with existing method, reaction condition of the present invention is mild, the reaction time is short, safety is good, simple operation, anti-
It answers efficient and catalyst cheap, is a kind of method with potential using value.
It is above-mentioned to apply example the invention is not limited in any way, it is all to be obtained by the way of small transformation using equivalent replacement or wait
Technical solution is all fallen in protection scope of the present invention.
Claims (10)
1. the technique that solventless method synthesizes 3- nitroquinoline derivatives, it is characterised in that：Under solvent-free conditions, nitroolefin with
[3+2] cycloaddition reaction occurs under the action of copper salt catalyst for the aryl azide of ortho position aldehyde radical substitution, and wherein nitroolefin is
Alkyl, substitution alkyl, aryl or substituted aryl substitution nitroolefin, ortho position aldehyde radical substitution aryl azide in aryl be aryl
Or substituted aryl.
2. technique according to claim 1, it is characterised in that：The copper salt catalyst is selected from CuI, CuCl, CuBr,
Cu2O or Cu (OTf)2。
3. technique according to claim 2, it is characterised in that：The copper salt catalyst is CuI.
4. according to claims 1 to 3 it is one of arbitrary described in technique, it is characterised in that：Copper salt catalyst dosage presses the amount of substance
It is calculated as 0.01-0.2 times of nitroolefin dosage.
5. technique according to claim 4, it is characterised in that：The copper salt catalyst dosage is calculated as nitre by the amount of substance
0.01 times of base alkene dosage.
6. technique according to claim 1, it is characterised in that：Reaction carries out within the temperature range of 80-130 DEG C.
7. technique according to claim 6, it is characterised in that：Reaction carries out under the conditions of 110 DEG C.
8. technique according to claim 1, it is characterised in that：The aryl azide of ortho position aldehyde radical substitution is calculated as by the amount of substance
1-5 times of nitroolefin dosage.
9. technique according to claim 8, it is characterised in that：The aryl azide of ortho position aldehyde radical substitution is calculated as by the amount of substance
1.5-2 times of nitroolefin dosage.
10. technique according to claim 1, it is characterised in that：Reaction time is 2-8 hours.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1073171A (en) * | 1991-10-28 | 1993-06-16 | 合成实验室公司 | Quinoline, its preparation method and the application in treatment thereof |
| CN107522659A (en) * | 2017-08-16 | 2017-12-29 | 云南大学 | 3 nitroquinoline analog derivatives and its preparation method and application |
-
2018
- 2018-07-11 CN CN201810758186.5A patent/CN108558750B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1073171A (en) * | 1991-10-28 | 1993-06-16 | 合成实验室公司 | Quinoline, its preparation method and the application in treatment thereof |
| CN107522659A (en) * | 2017-08-16 | 2017-12-29 | 云南大学 | 3 nitroquinoline analog derivatives and its preparation method and application |
Non-Patent Citations (4)
| Title |
|---|
| MANIAN RAJESH KUMAR ET AL.: "Consecutive Condensation, C-N and N-N Bond Formations: A Copper- Catalyzed One-Pot Three-Component Synthesis of 2H-Indazole", 《ORGANIC LETTER》 * |
| MARIA J. CLIMENT ET AL.: "Bifunctional acid–base ionic liquid for the one-pot synthesis of fine chemicals: Thioethers, 2H-chromenes and 2H-quinoline derivatives", 《APPLIED CATALYSIS A: GENERAL》 * |
| XIAN-FENG CAI ET AL.: "Asymmetric Transfer Hydrogenation of 3-Nitroquinolines: Facile Access to Cyclic Nitro Compounds with Two Contiguous Stereocenters", 《CHEM.ASIAN J.》 * |
| YOGESH GORIYA AND CHEPURI V. RAMANA: "2-Aroylindoles from o-bromochalcones via Cu(I)-catalyzed SNAr with an azide and intramolecular nitrene C-H insertion", 《CHEM. COMMUN.》 * |
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