CN106518887A - Method for establishing tetrahydroquinoline spiro framework under catalyst-free condition - Google Patents
Method for establishing tetrahydroquinoline spiro framework under catalyst-free condition Download PDFInfo
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- CN106518887A CN106518887A CN201611038032.6A CN201611038032A CN106518887A CN 106518887 A CN106518887 A CN 106518887A CN 201611038032 A CN201611038032 A CN 201611038032A CN 106518887 A CN106518887 A CN 106518887A
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- Prior art keywords
- tetrahydroquinoline
- reaction
- spirocyclic ring
- built under
- catalysts conditions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
Abstract
The invention discloses a method for establishing a tetrahydroquinoline spiro framework under a catalyst-free condition. According to the method, a reaction can be conducted under the conditions that no catalyst exists, the temperature is 25 DEG C, and the solvent is ethyl alcohol or water. According to the method for establishing the tetrahydroquinoline spiro framework under the catalyst-free condition, the [1,5]-hydrogen migration reaction in the water phase is achieved for the first time under the catalyst-free condition, raw materials are simple and easy to obtain, reaction conditions are mild, operation is easy and practical, the reaction activity is high, the raw materials are completely transformed, separation is convenient, the productivity is high, and the reaction has environment friendliness economical efficiency and is environmentally friendly.
Description
Technical field
The present invention relates to chemosynthesis technical field, more particularly to one kind is without structure tetrahydroquinoline spiral shell under catalysts conditions
The method of ring skeleton.
Background technology
Tetrahydroquinoline volution product is widely present in natural products and drug molecule, has pass closely with human lives
System.Without under the conditions of catalyst room temperature in cleaning solvent by Hydrogen transfer reaction come tetrahydrobiopterin synthesis quinoline spiro-compound, still
It is that there is in organic chemical synthesis a challenging problem.
Bibliography
(a) PengB, MaulideN, Chem.Eur.J.2013,19,13274.
(b)WangL.；XiaoJ.Adv.Synth.Catal.2014,356,1137.
(c) HaibachMC, SeidelD, Angew.Chem., Int.Ed.2014,53,4979.
(d) KwonSJ, KimDY, Chem.Rec.2016,16,1191.
(e) WangL, XiaoJ, Org.Chem.Front., 2016,3,635..
The content of the invention
It is an object of the invention to provide one kind is gone here and there by [1,5]-H migrations/cyclisation without in water phase/ethanol under catalysts conditions
The method that connection reaction builds tetrahydroquinoline spirocyclic ring scaffold.Present invention practicality simple to operate, yield are good, and react with green economy
Property, it is environmentally friendly, it is easy to industrialize.
It is a kind of in the method without tetrahydroquinoline spirocyclic ring scaffold is built under catalysts conditions, methods described without catalyst, reaction
Formula and condition are as follows：
In formula：
Temperature：25℃；
Solvent：Ethanol or water；
Time：48 hours；
Described R1 is a kind of substituent in methyl, methoxyl group, Cl, Br, trifluoromethyl or nitro；
Described R2 is methyl, methoxyl group, a kind of substituent in F, Cl, Br；
Described X is C, N, O；
Described n1For 0,1；
Described n2For 0,1；
Comprise the following steps：The 4 hydroxy coumarin of 0.2mmol neighbour's nafoxidine benzaldehydes and 0.3mmol is taken in tube sealing
In, the solvent of 2mL being added, is stirred at room temperature and is reacted, response situation is determined by TLC, reaction finishes to be entered with extractant
Row extraction, with desiccant dryness, filter, concentration, it is rapid cross silicagel column, finally with n-hexane and recrystallize with dichloromethane.
Preferably, the adjacent nafoxidine benzaldehyde and the mol ratio of coumarin derivatives are 1:1.5.
Preferably, the temperature range is 25～120 DEG C.
Preferably, the solvent can also be acetonitrile, DMF, DCM, DCE, toluene or tetrahydrofuran.
Preferably, the extractant is ethyl acetate.
Preferably, the drier is anhydrous magnesium sulfate.
Preferably, the reaction is obtained containing whorled tetrahydroquinoline with adjacent substituted-amino benzaldehyde for substituted cumarin
Compound, reaction temperature be 25 DEG C, reaction dissolvent be ethanol when result it is optimal, reach 92%, react for water when, reach 83%.
It is proposed by the present invention a kind of in the method without tetrahydroquinoline spirocyclic ring scaffold is built under catalysts conditions, realize first
[1,5]-Hydrogen transfer reaction in without water phase under catalysts conditions, raw material are simple and easy to get, and reaction condition is gentle, reality simple to operate
With reactivity is high, and raw material conversion is complete, and convenient separation, yield are high, and reacts with green economy, environmentally friendly.
Specific embodiment
The present invention is further explained with reference to specific embodiment.
Embodiment 1：The optimization of condition
Take 0.2mmol neighbour nafoxidine benzaldehyde and 0.3mmol 4 hydroxy coumarin in tube sealing, add 2mL it is molten
Agent, is stirred at room temperature and is reacted, and determines response situation by TLC.It is extracted with ethyl acetate after completion of the reaction, uses anhydrous sulphur
Sour magnesium is dried, filtration, concentration, rapid silicagel column excessively, finally with n-hexane and recrystallize with dichloromethane.
Under identical reaction conditions, solvent for use is different, and reaction yield is also different, and concrete yield is as follows：
Note：Yield is separation yield.
Embodiment 2：Without cascade reaction being migrated/being cyclized by [1,5]-H in water phase/ethanol under catalysts conditions build tetrahydrochysene
Quinoline spiro-compound
To separate yield, diastereomeric excess is determined yield with nuclear magnetic spectrogram.
Embodiment 3：
Nuclear magnetic resonance spectroscopy is carried out to product obtained in the present embodiment：
Isolatedyield:82%, yellowsolid；d.r.:70:30.1HNMR(500MHz,CDCl3)δ7.98
(dd, J=7.8,1.5Hz, 1H), 7.71 7.64 (m, 1H), 7.30 (t, J=7.4Hz, 1H), 7.21 7.13 (m, 2H), 7.07
(d, J=7.4Hz, 1H), 6.67 (t, J=7.4Hz, 1H), 6.61 (d, J=8.1Hz, 1H), 3.87 (dd, J=9.4,5.6Hz,
1H), 3.59 3.54 (m, 2H), 3.39 3.35 (m, 1H), 3.07 (d, J=16.4Hz, 1H), 2.06 1.99 (m, 1H), 1.96
(m, J=8.9,6.0,2.4Hz, 2H), 1.68 1.62 (m, 1H).
13CNMR(125MHz,CDCl3)δ192.79,164.95,155.33,143.30,137.42,128.44,
127.67,127.26,125.03,118.47,117.77,117.40,116.36,111.41,63.95,55.25,47.61,
36.37,28.16,23.51.
Embodiment 4：
Nuclear magnetic resonance spectroscopy is carried out to product obtained in the present embodiment：
Isolatedyield:73%, yellowsolid；d.r.:65:35.1HNMR(500MHz,CDCl3)δ8.01(d,
J=7.3Hz, 1H), 7.71 (t, J=7.3Hz, 1H), 7.32 (dd, J=18.1,10.8Hz, 2H), 7.22 (d, J=7.9Hz,
1H), 7.06 (d, J=7.0Hz, 1H), 6.81 (t, J=7.7Hz, 1H), 4.32 (dd, J=17.0,8.2Hz, 1H), 3.76 (d,
J=16.1Hz, 2H), 3.41 (s, 1H), 3.09 (d, J=16.8Hz, 1H), 2.15 (dt, J=20.5,10.3Hz, 1H), 1.95
(s, 2H), 1.79 (d, J=12.0Hz, 1H).
13CNMR(125MHz,CDCl3)δ192.50,167.75,155.55,140.87,137.56,129.03,
127.26,127.11,125.47,125.27,122.49,120.44,119.02,117.83,69.26,54.43,53.21,
35.18,28.30,23.60.
Embodiment 5：
Nuclear magnetic resonance spectroscopy is carried out to product obtained in the present embodiment：
Isolatedyield:75%, yellowsolid；d.r.:71:29.1HNMR(500MHz,CDCl3)δ8.01(d,
J=7.8Hz, 1H), 7.70 (t, J=7.8Hz, 1H), 7.33 (t, J=7.5Hz, 1H), 7.23 (d, J=8.3Hz, 1H),
7.11 7.06 (m, 1H), 6.75 (t, J=8.7Hz, 1H), 6.53 (d, J=8.2Hz, 1H), 3.74 (dd, J=8.8,5.6Hz,
1H), 3.56 (t, J=7.9Hz, 1H), 3.42 (d, J=8.7Hz, 1H), 3.37 (d, J=6.3Hz, 2H), 2.03 (dd, J=
16.4,7.2Hz, 1H), 2.00 1.92 (m, 2H), 1.65 (dd, J=18.8,9.0Hz, 1H).
13CNMR(125MHz,CDCl3)δ192.27,165.19,155.33,144.47,137.63,134.05,
127.78,127.40,125.21,118.54,117.85,117.24,117.17,109.93,64.04,55.55,47.77,
33.24,28.23,23.48.
The above, the only present invention preferably specific embodiment, but protection scope of the present invention is not limited thereto,
Any those familiar with the art the invention discloses technical scope in, technology according to the present invention scheme and its
Inventive concept equivalent or change in addition, should all be included within the scope of the present invention.
Claims (7)
1. it is a kind of in the method without tetrahydroquinoline spirocyclic ring scaffold is built under catalysts conditions, it is characterised in that methods described is without urging
Agent, reaction equation and condition it is as follows：
In formula：
Temperature：25℃；
Solvent：Ethanol or water；
Time：48 hours；
Described R1 is a kind of substituent in methyl, methoxyl group, Cl, Br, trifluoromethyl or nitro；
Described R2 is methyl, methoxyl group, a kind of substituent in F, Cl, Br；
Described X is C, N, O；
Described n1For 0,1；
Described n2For 0,1；
Comprise the following steps：Take 0.2mmol neighbour nafoxidine benzaldehyde and 0.3mmol 4 hydroxy coumarin in tube sealing, plus
Enter the solvent of 2mL, be stirred at room temperature and reacted, response situation is determined by TLC, reaction is finished and extracted with extractant
Take, with desiccant dryness, filtration, concentration, rapid silicagel column excessively, finally with n-hexane and recrystallize with dichloromethane.
2. according to claim 1 a kind of in the method without tetrahydroquinoline spirocyclic ring scaffold is built under catalysts conditions, which is special
Levy and be, the adjacent nafoxidine benzaldehyde is 1 with the mol ratio of coumarin derivatives:1.5.
3. according to claim 1 a kind of in the method without tetrahydroquinoline spirocyclic ring scaffold is built under catalysts conditions, which is special
Levy and be, the temperature range is 25～120 DEG C.
4. according to claim 1 a kind of in the method without tetrahydroquinoline spirocyclic ring scaffold is built under catalysts conditions, which is special
Levy and be, the solvent can also be acetonitrile, DMF, DCM, DCE, toluene or tetrahydrofuran.
5. according to claim 1 a kind of in the method without tetrahydroquinoline spirocyclic ring scaffold is built under catalysts conditions, which is special
Levy and be, the extractant is ethyl acetate.
6. according to claim 1 a kind of in the method without tetrahydroquinoline spirocyclic ring scaffold is built under catalysts conditions, which is special
Levy and be, the drier is anhydrous magnesium sulfate.
7. according to claim 1 a kind of in the method without tetrahydroquinoline spirocyclic ring scaffold is built under catalysts conditions, which is special
Levy and be, the reaction is obtained containing whorled 3,4-tetrahydroquinoline compounds with adjacent substituted-amino benzaldehyde for substituted cumarin,
When reaction temperature is 25 DEG C, reaction dissolvent is ethanol, result is optimal, reaches 92%, react for water when, reach 83%.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108586424A (en) * | 2018-07-04 | 2018-09-28 | 青岛农业大学 | A kind of Benzylation synthetic method of phenol compound |
| CN108586457A (en) * | 2018-07-06 | 2018-09-28 | 青岛农业大学 | A kind of indoles carbocyclic ring based on α hydrogen migration strategies of nitrogen-atoms goes aromatization synthetic method |
| CN108640918A (en) * | 2018-07-06 | 2018-10-12 | 青岛农业大学 | A kind of synthetic method of the azacyclo- substitution to quinone skeleton spiro-compound |
| CN110684031A (en) * | 2019-08-14 | 2020-01-14 | 西北大学 | Asymmetric synthesis method of trans-tetrahydropyranyl tetrahydroquinoline derived chiral compound |
-
2016
- 2016-11-23 CN CN201611038032.6A patent/CN106518887A/en active Pending
Non-Patent Citations (4)
| Title |
|---|
| E.V.D YACHENKO,ET AL.,: "tert-Amino effect in heterocyclic chemistry.Synthesis of hydrogenated spiro derivatives of quinolines", 《RUSSIAN CHEMICAL BULLETIN, INTERNATIONAL EDITION》 * |
| K.A.KRASNOV，ET AL.,: "Synthesis of Spiroheterocyclic Systems from Barbituric Acids and N,N-Disubstituted o-Aminobenzaldehydes", 《RUSSIAN JOURNAL OF ORGANIC CHEMISTRY》 * |
| SERGEY V. RYABUKHIN ET AL.,: "A One-Pot Fusion of Nitrogen-Containing Heterocycles", 《SYNTHESIS》 * |
| T. V. GLUKHAREVA,ET AL.,: "SYNTHESIS OF SPIRO DERIVATIVES OF PYRROLO[1,2-a]QUINOLINE", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108586424A (en) * | 2018-07-04 | 2018-09-28 | 青岛农业大学 | A kind of Benzylation synthetic method of phenol compound |
| CN108586424B (en) * | 2018-07-04 | 2020-07-21 | 青岛农业大学 | Benzylation synthesis method of phenol compounds |
| CN108586457A (en) * | 2018-07-06 | 2018-09-28 | 青岛农业大学 | A kind of indoles carbocyclic ring based on α hydrogen migration strategies of nitrogen-atoms goes aromatization synthetic method |
| CN108640918A (en) * | 2018-07-06 | 2018-10-12 | 青岛农业大学 | A kind of synthetic method of the azacyclo- substitution to quinone skeleton spiro-compound |
| CN108586457B (en) * | 2018-07-06 | 2020-05-19 | 青岛农业大学 | indole carbocycle dearomatization synthesis method based on nitrogen atom α hydrogen migration strategy |
| CN108640918B (en) * | 2018-07-06 | 2020-05-19 | 青岛农业大学 | Synthetic method of nitrogen heterocyclic ring substituted p-quinone skeleton spiro-compound |
| CN110684031A (en) * | 2019-08-14 | 2020-01-14 | 西北大学 | Asymmetric synthesis method of trans-tetrahydropyranyl tetrahydroquinoline derived chiral compound |
| CN110684031B (en) * | 2019-08-14 | 2021-07-02 | 西北大学 | Asymmetric synthesis method of trans-tetrahydrofuran/pyranotetrahydroquinoline derived chiral compound |
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