CN115772169A - Indoline [2,1-a ] isoquinoline derivative, preparation method and application - Google Patents
Indoline [2,1-a ] isoquinoline derivative, preparation method and application Download PDFInfo
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- CN115772169A CN115772169A CN202111037197.2A CN202111037197A CN115772169A CN 115772169 A CN115772169 A CN 115772169A CN 202111037197 A CN202111037197 A CN 202111037197A CN 115772169 A CN115772169 A CN 115772169A
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- indoline
- isoquinoline derivative
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- alkoxy
- isoquinoline
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- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title claims abstract description 31
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 48
- 239000002994 raw material Substances 0.000 claims abstract description 40
- 239000001257 hydrogen Substances 0.000 claims abstract description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 28
- 125000003118 aryl group Chemical group 0.000 claims abstract description 27
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 26
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 26
- 239000000460 chlorine Substances 0.000 claims abstract description 25
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 11
- 125000006575 electron-withdrawing group Chemical group 0.000 claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000011737 fluorine Substances 0.000 claims abstract description 5
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 9
- 238000006243 chemical reaction Methods 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 230000035484 reaction time Effects 0.000 claims description 11
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 8
- 150000002825 nitriles Chemical class 0.000 claims description 7
- 238000007146 photocatalysis Methods 0.000 claims description 7
- 230000001699 photocatalysis Effects 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000003792 electrolyte Substances 0.000 claims description 5
- 239000000919 ceramic Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 239000002131 composite material Substances 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 3
- 239000000758 substrate Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 150000002537 isoquinolines Chemical class 0.000 description 49
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 20
- 150000002431 hydrogen Chemical class 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- -1 class of nitrogen-containing heterocyclic compounds Chemical class 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 3
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000002476 indolines Chemical class 0.000 description 2
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000003672 processing method Methods 0.000 description 2
- BESQLCCRQYTQQI-UHFFFAOYSA-N propan-2-yl 2-cyanoacetate Chemical compound CC(C)OC(=O)CC#N BESQLCCRQYTQQI-UHFFFAOYSA-N 0.000 description 2
- NLFIMXLLXGTDME-UHFFFAOYSA-N propyl 2-cyanoacetate Chemical compound CCCOC(=O)CC#N NLFIMXLLXGTDME-UHFFFAOYSA-N 0.000 description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- JFDUBCIPPATLNR-UHFFFAOYSA-N 2-phenyl-3,4-dihydro-1h-isoquinoline-1-carbonitrile Chemical compound C1CC2=CC=CC=C2C(C#N)N1C1=CC=CC=C1 JFDUBCIPPATLNR-UHFFFAOYSA-N 0.000 description 1
- MZXDPTWGJXNUMW-UHFFFAOYSA-N 7h-pyrido[3,2-c]carbazole Chemical group C1=CC=NC2=C3C4=CC=CC=C4NC3=CC=C21 MZXDPTWGJXNUMW-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Abstract
The invention belongs toThe field of machine synthesis, in particular to indoline [2,1-a ]]Isoquinoline derivative, preparation method and application thereof, indoline [2,1-a]An isoquinoline derivative having the structural formula:
wherein R is 1 Including alkyl, alkoxy, hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano; r 2 Including aryl, alkoxy, hydrogen, chlorine or bromine; r 3 Including aryl, alkoxy, hydrogen, chlorine or bromine; r 4 Including electron withdrawing groups; r 1 Is located in indoline [2,1-a]The C8, C9, C10 or C11 position of the isoquinoline derivative; r 2 Or R 3 In the corresponding indoline [2,1-a ]]At C2 or C3 position of isoquinoline derivative, R 2 Or R 3 May be the same or different. The product of the invention is a novel product, the preparation method is green and efficient, the preparation condition is mild, the requirement on equipment is low, the operation is simple and convenient, the application range of the substrate is wide, the price of the raw material is low, the manufacturing cost is low, the yield is high, the industrial mass production can be realized, and the invention has wide application prospect.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to an indoline [2,1-a ] isoquinoline derivative, a preparation method and application thereof.
Background
Fused ring indole and derivatives thereof are an extremely important class of nitrogen-containing heterocyclic compounds and widely exist in various natural products. Most of the compounds have unique physicochemical properties and biological activities, and have important application in the fields of organic synthetic chemistry, material chemistry, pharmaceutical chemistry and the like, so that the synthesis work of the compounds is always concerned.
The indosoquinoline derivatives, as an important polycyclic indole derivative, show better pharmaceutical activity in the aspects of treating multiple sclerosis and hepatitis C, resisting proliferation of breast cancer cells, resisting viruses and the like, and are an 'advantageous structure' for developing novel drug lead molecules. The currently reported method for constructing the fused ring indoloquinoline skeleton generally has the problems of long steps, harsh reaction conditions, heavy metal residue and the like.
Disclosure of Invention
The invention aims to solve the technical problem and provides a novel indoline [2,1-a ] isoquinoline derivative, a preparation method and application thereof.
In order to solve the above technical problems, the present invention provides a technical solution: the structural formula of the indoline [2,1-a ] isoquinoline derivative and the indoline [2,1-a ] isoquinoline derivative is as follows:
wherein R is 1 Including alkyl, alkoxy, hydrogen, fluoro, chloro, bromo, trifluoromethyl or cyano; r 2 Including aryl, alkoxy, hydrogen, chlorine or bromine; r 3 Including aryl, alkoxy, hydrogen, chlorine or bromine; r 4 Including electron withdrawing groups; r 1 Is located in indoline [2,1-a]The C8, C9, C10, C11 positions of the isoquinoline derivative; r 2 Or R 3 Is located in indoline [2,1-a]C2, C3 position of isoquinoline derivatives, R 2 Or R 3 May be the same or different.
Further, R 1 The alkyl group of (A) includes C1-C8 alkyl groups, R 1 The alkoxy group of (b) includes a C1-C8 alkoxy group; r 2 The aryl group of (A) includes phenyl or a plurality of aryl groups containing a pull-electron group, R 2 The alkoxy group of (b) includes a C1-C8 alkoxy group; r 3 The aryl group of (A) includes phenyl or a plurality of aryl groups containing a pull-electron group, R 3 The alkoxy group of (A) includes C1-C8 alkoxy groups; r is 4 The electron-withdrawing group comprises a cyano group and a C1-C8 alkyl ester group.
Further, R 1 The C1-C8 alkyl group of (A) includes tert-butyl, methyl, ethyl, isopropyl or n-butyl, R 1 The C1-C8 alkoxy group of (1) includes methoxy or ethoxy; r 2 The C1-C8 alkoxy group of (1) includes methoxy, ethoxy; r 3 The C1-C8 alkoxy group of (1) includes a methoxy group or an ethoxy group.
Wherein, the indoline [2,1-a ] isoquinoline derivative comprises:
the invention also comprises a second technical scheme, a preparation method of the indoline [2,1-a ] isoquinoline derivative, which comprises the following steps: n-aryl isoquinoline and organic nitrile are taken as raw materials, and are subjected to photoelectrocatalysis reaction at room temperature to obtain indoline [2,1-a ] isoquinoline derivatives; the reaction formula of the synthesis process is as follows:
wherein, indoline [2,1-a]The isoquinoline derivative is compound 4; r 1 Including alkyl, alkoxy, hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano; r 2 Including aryl, alkoxy, hydrogen, chlorine or bromine; r 3 Including aryl, alkoxy, hydrogen, chlorine or bromine; r 4 Including electron withdrawing groups; r 1 Is located in indoline [2,1-a]The C8, C9, C10 or C11 position of the isoquinoline derivative; r 2 Or R 3 Is located in indoline [2,1-a]At C2 or C3 position of isoquinoline derivatives, R 2 Or R 3 May be the same or different.
The photoelectrocatalysis comprises photocatalysis and electrocatalysis, and the photocatalysis adopts visible light catalysis; an electrocatalytic unbiased electrode pair, the anode of which comprises BiVO 4 Photoanode or BiVO 4 The composite photo-anode of (1).
Wherein a counter electrode of the electrode pair comprises platinum.
Wherein, biVO 4 The compound comprises BiVO 4 And in BiVO 4 FTO, ITO or conductive ceramic layer on the surface.
Wherein the electrolyte for the photoelectrocatalysis reaction comprises Et 4 NBr、Et 4 NCl、n-Bu 4 NBr、n-Bu 4 NCl, KCl or NH 4 Any one or a mixture of more of Cl.
Wherein the visible light catalytic light source comprises white light or monochromatic light.
Wherein the reaction time is 4-12 hours. The reaction time can be determined by TLC or GC-MS detection according to the difference in reactivity, and is not particularly limited herein, and the reaction time of 4 to 12 hours is provided as a set range of the reaction time in general.
Wherein the solvent of the reaction comprises an alcohol; preferably, the solvent comprises any one or more of ethanol, methanol and isopropanol. The solvent adopted by the invention is alcohol, so that the toxicity is low, and the reaction can be carried out in a green way.
Wherein the organic nitrile source comprises malononitrile, methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate or isopropyl cyanoacetate.
The invention also comprises a third technical scheme, and a compound applied to medicines comprises the indoline [2,1-a ] isoquinoline derivative.
Has the advantages that:
(1) The indoline [2,1-a ] isoquinoline derivative, cyano-substituted indoline [2,1-a ] isoquinoline or cyano-substituted indoline [2,1-a ] isoquinoline which is jointly substituted by other electron-withdrawing groups (such as ester groups) and the like are novel compounds and can be widely applied to organic chemistry, material chemistry and pharmaceutical chemistry.
(2) The preparation method of the indoline [2,1-a ] isoquinoline derivative is a novel preparation method, can realize coupling/ring closure of N-aryl tetrahydroisoquinoline and organic nitrile which are cheap and easy to obtain under the room temperature condition by visible light induced photoelectrocatalysis without external bias voltage and heating, and can prepare a plurality of indoline [2,1-a ] isoquinoline compounds with high efficiency in one pot. The method has good substrate and functional group tolerance, can realize multiple recycling by using the catalyst, is green and efficient, has mild preparation conditions, low requirements on equipment, simple and convenient operation, wide substrate application range, low raw material price, low manufacturing cost and higher yield, can be used for industrial mass production, and has wide application prospect.
(3) Indolines of the invention [2,1-a]The preparation method of the isoquinoline derivative adopts photoelectrocatalysis, and the adopted catalyst is BiVO 4 Or comprises BiVO 4 A complex of (2), bismuth vanadateThe photo-anode has low price, good stability, a band gap of 2.4eV, good response to visible light, and electric potential matched with material electric potential. Using BiVO 4 Or comprises BiVO 4 The compound can be used as a catalyst when being used as a photoanode, so that the compound can be catalyzed at room temperature under the irradiation of visible light without external bias voltage and heating, and can also be used as the photoanode to generate electrocatalysis, namely, the photoanode is excited by visible light to generate a hole-electron pair, and the photoproduction electron is transferred to a counter electrode through a lead, so that the coupling of the electron-hole pair can be reduced, and the reaction rate is accelerated; on the other hand, the oxidation and reduction reactions in the photoreaction are separated to promote the reaction. BiVO adopted by preparation method of invention 4 The photo-anode catalyst has low cost, is easy to prepare and recycle, and can be repeatedly used.
(4) The preparation method of the indoline [2,1-a ] isoquinoline derivative has low preparation time and can improve the preparation efficiency.
Drawings
FIG. 1 shows an embodiment of the present invention in which the photo anode is BiVO 4 FTO yield patterns of the resulting products were tested in duplicate.
Detailed Description
The following are specific examples of the invention, which are intended to be illustrative of the invention only and not limiting. Modifications and adaptations of the invention in reagent applications that may occur to those skilled in the art are intended to be within the scope of the invention.
The embodiment of the invention provides an indoline [2,1-a ] isoquinoline derivative, wherein the structural formula of the indoline [2,1-a ] isoquinoline derivative is as follows:
wherein R is 1 Including alkyl, alkoxy, hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano; r is 2 Including aryl, alkoxy, hydrogen, chlorine or bromine; r 3 Including aryl, alkoxy, hydrogen, chlorine or bromine; r 4 Including electron withdrawing groups; r 1 In indolines[2,1-a]The C8, C9, C10 or C11 position of the isoquinoline derivative; r 2 Or R 3 Is located in indoline [2,1-a]At C2 or C3 position of isoquinoline derivatives, R 2 Or R 3 May be the same or different.
Further, R 1 The alkyl group of (A) includes C1-C8 alkyl groups, R 1 The alkoxy group of (A) includes C1-C8 alkoxy groups; r 2 The aryl group includes phenyl or a plurality of aryl groups containing a push-pull electron group, R 2 The alkoxy group of (A) includes C1-C8 alkoxy groups; r 3 The aryl group of (A) includes phenyl or a plurality of aryl groups containing a pull-electron group, R 3 The alkoxy group of (A) includes C1-C8 alkoxy groups; r is 4 The electron-withdrawing group comprises a cyano group and a C1-C8 alkyl ester group.
Further, R 1 The C1-C8 alkyl group of (A) includes t-butyl, methyl, ethyl, isopropyl or n-butyl, R 1 The C1-C8 alkoxy group of (1) includes methoxy or ethoxy; r 2 The C1-C8 alkoxy group of (1) includes methoxy or ethoxy; r 3 The C1-C8 alkoxy group of (b) includes methoxy or ethoxy.
The invention also comprises a second technical scheme, a preparation method of the indoline [2,1-a ] isoquinoline derivative, which comprises the following steps: n-aryl tetrahydroisoquinoline and organic nitrile are taken as raw materials, and a photoelectrocatalysis reaction is adopted at room temperature to obtain the indoline [2,1-a ] isoquinoline derivative; the reaction formula of the synthesis process is as follows:
wherein, indoline [2,1-a]The isoquinoline derivative is a compound 4; r 1 Including alkyl, alkoxy, hydrogen, fluoro, chloro, bromo, trifluoromethyl or cyano; r 2 Including aryl, alkoxy, hydrogen, chlorine or bromine; r is 3 Including aryl, alkoxy, hydrogen, chlorine or bromine; r is 4 Including electron withdrawing groups; r 1 Is located in indoline [2,1-a]The C8, C9, C10 or C11 position of the isoquinoline derivative; r 2 Or R 3 Is located in indoline [2,1-a]At C2 or C3 position of isoquinoline derivatives, R 2 Or R 3 Can be the same as orMay be different.
Specifically, when R is in the preparation method of the present invention 3 In the case of hydrogen, the reaction formula of the synthesis process is
The photoelectrocatalysis comprises photocatalysis and electrocatalysis, and the photocatalysis adopts visible light photocatalysis; an electrocatalytic unbiased electrode pair, the anode of which comprises BiVO 4 Photoanode or BiVO 4 The composite photo-anode of (1).
Wherein a counter electrode of the electrode pair comprises platinum.
Wherein, biVO 4 The compound comprises BiVO 4 And in BiVO 4 FTO, ITO or conductive ceramic layer on the surface.
Wherein the electrolyte for photoelectrocatalysis reaction comprises Et 4 NBr、Et 4 NCl、n-Bu 4 NBr、n-Bu 4 NCl, KCl or NH 4 Any one or a mixture of more of Cl.
The visible light catalyzed light source includes white light or monochromatic light, for example, where the monochromatic light may be blue light, green light, etc.
Wherein the reaction time is 4-12 hours. The reaction time can be determined by TLC or GC-MS detection according to the difference in reactivity, and is not particularly limited herein, and the reaction time of 4 to 12 hours is provided as a set range of the reaction time in general.
Wherein the solvent of the reaction comprises an alcohol; preferably, the solvent comprises any one or more of ethanol, methanol and isopropanol. The solvent adopted by the invention is alcohol, so that the toxicity is low, and the reaction can be carried out in a green way.
Wherein the organic nitrile source comprises malononitrile, methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate or isopropyl cyanoacetate.
In order to facilitate understanding of the above technical solutions, the present invention further provides specific examples to illustrate the above technical solutions, but the present invention is not limited to the following specific examples.
Example 1
The embodiment of the invention provides indoline [2,1-a ] isoquinoline derivatives, in particular 12,12 (6H) -dicyano-5, 12a-indoline [2,1-a ] isoquinoline (4 a), and the structural formula of the derivatives is as follows:
the preparation method of the indoline [2,1-a ] isoquinoline derivative comprises the following steps:
0.2mmol of N-aryltetrahydroisoquinoline and 0.3mmol of malononitrile as raw materials were sequentially added to a quartz reaction tube, and ammonium chloride (0.1M) and 5mL of an ethanol solution were added thereto. With BiVO 4 the/FTO is a photo-anode, the platinum sheet is a counter electrode, no external bias voltage is applied, and the reaction is carried out under the irradiation of visible light. After completion of the reaction, the electrode was washed with dichloromethane, the reaction solution was extracted with dichloromethane (5 mL. Times.3) and saturated brine (5 mL. Times.2) in this order, and the organic phase was extracted with anhydrous Na 2 SO 4 And (5) drying. The product can be obtained in 72% yield by separation and purification by column chromatography (eluent: ethyl acetate/petroleum ether 1/30-1/10, v/v). Wherein, the raw materials adopted in the embodiment of the invention are shown in table 1, the structural formula of the obtained product is shown in table 1, and the yield of the obtained product is shown in table 1.
The reaction formula of the synthesis process is as follows:
wherein R is 3 Is hydrogen, R 2 Is hydrogen, R 1 Is hydrogen, R 4 Is a nitrile group.
The result of structural characterization of the product is:
5,12a-dihydroindolo[2,1-a]isoquinoline-12,12(6H)-dicarbonitrile(4a)White solid(39.2mg,72％).mp.125-126℃. 1 H NMR(400MHz,CDCl 3 ):δ7.66-7.45(m,2H),7.40-7.21(m,4H),6.92(t,J＝7.5Hz,1H),6.75(d,J＝7.8Hz,1H),5.19(s,1H),3.91-3.76(m,1H),3.27-3.10(m,2H),2.94-2.82(m,1H). 13 C NMR(100MHz,CDCl 3 ):δ149.5,135.6,132.2,129.7,129.6,128.9,127.2,125.6,124.9,122.0,120.5,115.1,112.2,109.6,72.0,42.6,42.5,28.7.HRMS(ESI),calcd.for C 18 H 14 N 3 (M+H) + :272.1182,found:272.1183.
in the above synthesis method, the reaction time can be determined by TLC or GC-MS detection according to the difference in substrate reactivity by those skilled in the art, and is not particularly limited herein, and the reaction time can be generally set to 4 to 12 hours.
In the examples of the present application, the electrolyte is ammonium chloride, and in other examples, the electrolyte may be selected from the group consisting of Et 4 NBr、Et 4 NCl、n-Bu 4 NBr、n-Bu 4 NCl or KCl; the solvent in the embodiment of the present application is ethanol, and in other embodiments, the solvent may also be selected from methanol or isopropanol.
The indoline [2,1-a ] isoquinoline derivative prepared by the embodiment of the application is 12,12 (6H) -dicyano-5, 12a-indoline [2,1-a ] isoquinoline, and can be applied to the fields of medicines, organic chemistry and material chemistry.
The photo-anode adopted by the embodiment of the invention is BiVO 4 the/FTO is a sheet structure, and in other embodiments, the photoanode can also be BiVO 4 ITO or BiVO 4 Conductive ceramic layer, the photo-anode of the embodiment of the invention is easy to recycle. Specifically, the BiVO recovered in the embodiment of the invention 4 the/FTO photo-anode still has good circulating catalytic capability, so that the embodiment of the invention further provides BiVO 4 The circulating catalytic capability of the FTO photo-anode is tested, and the specific test conditions and test results are as follows:
to-be-indoline [2,1-a]After the reaction of the preparation method of the isoquinoline derivative is finished, biVO is added 4 Taking out the/FTO photo-anode plate from the reaction solution, washing with dichloromethane for 3 times, drying, and adding BiVO 4 the/FTO photo-anode sheet is used for the indoline [2,1-a]The preparation method of the isoquinoline derivative is tested for 10 times repeatedly, and the isoquinoline derivative still maintains extremely high catalytic reaction capability and can convert raw materials into corresponding raw materials with higher yieldThe yield of the obtained product 4 is kept between 69 and 73 percent; the yields of product 3a and product 4a from repeat test 10 are given in figure 1, where product 4a is: 12,12 (6H) -dicyano-5, 12a-indoline [2,1-a]Isoquinoline (4 a); the product 3a is:
wherein R is 1 And R 2 All are hydrogen, and product 3a is named: 2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile.
Table 1 synthesis of indoline [2,1-a ] isoquinoline derivatives starting materials, products and yields.
Example 2
In the embodiment of the invention, the indoline [2,1-a ] isoquinoline derivative has a structural general formula as follows:
wherein R is 1 Is tert-butyl group ( t Bu), and is located at C10 position; r is 2 Is hydrogen; r 3 Is hydrogen; r is 4 Is cyano.
The embodiment of the invention provides a preparation method of indoline [2,1-a ] isoquinoline derivative, the synthesis reaction formula is as follows:
the preparation method specifically comprises the following steps: 0.2mmol of 2-arylisoquinoline (raw material 1 having the structural formula of example 2 in Table 2) and 0.3mmol of an organic nitrile (raw material 2 having the structural formula of example 2 in Table 2) were sequentially charged into a quartz reaction tube, and ammonium chloride (0.1M) and 5mL of an ethanol solution were added. With BiVO 4 the/FTO is a photo-anode, the platinum sheet is a counter electrode, no external bias voltage is applied, and the reaction is carried out under the irradiation of visible light. After completion of the reaction, the electrode was washed with dichloromethane, the reaction mixture was extracted with dichloromethane (5 mL. Times.3) and saturated brine (5 mL. Times.2) in this order, and the organic phase was extracted with anhydrous Na 2 SO 4 And (5) drying. The product (product of example 2 with the formula shown in Table 2) can be obtained in 66% yield by separation and purification by column chromatography (eluent: ethyl acetate/petroleum ether 1/30-1/10, v/v).
Example 3
The difference from example 2 is that indoline [2,1-a ]]In the structural formula of the isoquinoline derivative, R 1 Is ethyl (Et). The raw material in the preparation method is the raw material of example 3 in the table 2, and the yield of the product is 61%. The rest is the same as embodiment 2, and is not described herein again.
Example 4
The difference from example 2 is that indoline [2,1-a ]]In the structural formula of the isoquinoline derivative, R 1 Is methyl (Me). The raw material in the preparation method is the raw material of example 4 in the table 2, and the yield of the product is 68%. The rest is the same as embodiment 2, and is not described herein again.
Example 5
The difference from example 2 is that indoline [2,1-a]In the structural formula of the isoquinoline derivative, R 1 Is fluorine (F). The raw material in the preparation method is the raw material of example 5 in the table 2, and the yield of the obtained product is 77%. The rest is the same as embodiment 2, and is not described herein again.
Example 6
The difference from example 2 is that indoline [2,1-a]In the structural formula of the isoquinoline derivative, R 1 Is chlorine (Cl). In the preparation methodUsing the starting material of example 6 in table 2, the product was obtained in a yield of 77%. The rest is the same as embodiment 2, and is not described herein again.
Example 7
The difference from example 2 is that indoline [2,1-a]In the structural formula of the isoquinoline derivative, R 1 Is bromine (Br). The starting material in the preparation process used the starting material of example 7 in table 2, and the product was obtained in 74% yield. The rest is the same as embodiment 2, and is not described herein again.
Example 8
The difference from example 2 is that indoline [2,1-a]In the structural formula of the isoquinoline derivative, R 1 Is trifluoromethyl (CF) 3 ). The raw material in the preparation method is the raw material of example 8 in the table 2, and the yield of the product is 20%. The rest is the same as embodiment 2, and is not described herein again.
Example 9
The difference from example 2 is that indoline [2,1-a]In the structural formula of the isoquinoline derivative, R 1 Is methoxy (OMe) and is located at the C9-or C11-position, indoline [2,1-a of the present examples]Isoquinoline derivatives include: 12,12 (6H) -dicyano-11-methoxy-5, 12a-indoline [2,1-a]Isoquinoline and 12,12 (6H) -dicyano-9-methoxy-5, 12a-indoline [2,1-a]An isoquinoline. The raw material in the preparation method adopts the raw material of example 9 in the table 2, and the yield of the obtained product is 76%. The rest is the same as embodiment 2, and is not described herein again.
Example 10
The difference from example 2 is that indoline [2,1-a]In the structural formula of the isoquinoline derivative, R 1 Is bromine (Br) and is located at the C9-or C11-position, indoline [2,1-a of the examples]Isoquinoline derivatives include: 12,12 (6H) -dicyano-11-bromo-5, 12a-indoline [2,1-a]Isoquinoline and 12,12 (6H) -dicyano-9-bromo-5, 12a-indoline [2,1-a]An isoquinoline. The starting material in the preparation process used the starting material of example 10 in table 2, and the yield of the product obtained was 52%. The rest is the same as embodiment 2, and is not described herein again.
Example 11
And the embodiments2 the difference is that the indoline [2,1-a ]]In the structural formula of the isoquinoline derivative, R 2 Is bromine (Br) and is located at the C3 position. The raw material in the preparation method is the raw material of example 11 in the table 2, and the yield of the obtained product is 66%. The rest is the same as embodiment 2, and is not described herein again.
Example 12
The difference from example 2 is that indoline [2,1-a ]]In the structural formula of the isoquinoline derivative, R 2 Is bromine (Br) and is located at the C2 position. The raw material in the preparation method is the raw material of example 12 in the table 2, and the yield of the product is 85%. The rest is the same as embodiment 2, and is not described herein again.
Example 13
The difference from example 2 is that indoline [2,1-a]In the structural formula of the isoquinoline derivative, R 2 Is chlorine (Cl) and is located at the C2 position. The raw material in the preparation method adopts the raw material of example 13 in the table 2, and the yield of the obtained product is 65%. The rest is the same as embodiment 2, and is not described herein again.
Example 14
The difference from example 2 is that indoline [2,1-a]In the structural formula of the isoquinoline derivative, R 2 Is aryl (Ph) and is located at the C2 position. The starting material in the preparation process used the starting material of example 14 in Table 2, and the product was obtained in 51% yield. The rest is the same as embodiment 2, and is not described herein again.
Example 15
The difference from example 2 is that indoline [2,1-a]In the structural formula of the isoquinoline derivative, R 2 Is methoxy (MeO), R 3 Methoxy (MeO) at the C2 and C3 positions, respectively. The raw material in the preparation method is the raw material of example 15 in the table 2, and the yield of the product is 54 percent. The rest is the same as embodiment 2, and is not described herein again.
Example 16
The difference from example 2 is that indoline [2,1-a]In the structural formula of the isoquinoline derivative, R 4 As methyl acetate (MeOOC). The raw materials in the preparation method adopt the raw materials of example 16 in the table 2, the yield of the obtained product is 38 percent, and the obtained product is dextrorotatory and dextrorotatoryThe ratio of levorotatory to levorotatory is 4:1. the rest is the same as embodiment 2, and is not described herein again.
Example 17
The difference from example 2 is that indoline [2,1-a ]]In the structural formula of the isoquinoline derivative, R 2 Is bromine (Br), located at the C2 position; r 4 As methyl acetate (MeOOC). The raw materials in the preparation method adopt the raw materials of example 17 in the table 2, the yield of the obtained product is 68 percent, and the ratio of dextrorotation to levorotation of the obtained product is 4:1. the rest is the same as embodiment 2, and is not described herein again.
Example 18
The difference from example 2 is that indoline [2,1-a ]]In the structural formula of the isoquinoline derivative, R 2 Is bromine (Br), located at the C2 position; r 4 Was ethyl acetate (EtOOC). The raw materials in the preparation method adopt the raw materials in the example 18 in the table 2, the yield of the obtained product is 56 percent, and the ratio of dextrorotation to levorotation of the obtained product is 4:1. the rest is the same as embodiment 2, and is not described herein again.
Example 19
The difference from example 2 is that indoline [2,1-a]In the structural formula of the isoquinoline derivative, R 2 Is bromine (Br) at the C2 position; r 4 Is n-propyl acetate: ( n PrOOC). The raw materials in the preparation method adopt the raw materials in the example 19 in the table 2, the yield of the obtained product is 60 percent, and the ratio of dextrorotation to levorotation of the obtained product is 4:1. the rest is the same as embodiment 2, and the description is omitted.
Example 20
The difference from example 2 is that indoline [2,1-a]In the structural formula of the isoquinoline derivative, R 2 Is bromine (Br) at the C2 position; r is 4 Is isopropyl acetate ( i PrOOC). The raw materials in the preparation method adopt the raw materials in the example 20 in the table 2, the yield of the obtained product is 60 percent, and the ratio of dextrorotation to levorotation of the obtained product is 3:1. the rest is the same as embodiment 2, and is not described herein again.
The synthesis method has the advantages of cheap and easily-obtained raw materials, green reaction conditions, wide substrate applicability, high synthesis yield, recyclable catalytic system and the like, and has wide application prospect.
In light of the above teachings, those skilled in the art will readily appreciate that the invention can be practiced with other materials, or with equivalents thereof, or with other processing methods, or with equivalents thereof, and that the invention can be practiced with upper and lower limits and ranges for the parameters of the materials and processing methods, which are not specifically recited herein.
Claims (10)
1. Indoline [2,1-a ] isoquinoline derivative is characterized in that the indoline [2,1-a ] isoquinoline derivative has a structural formula as follows:
wherein R is 1 Including alkyl, alkoxy, hydrogen, fluoro, chloro, bromo, trifluoromethyl or cyano;
R 2 including aryl, alkoxy, hydrogen, chlorine or bromine;
R 3 including aryl, alkoxy, hydrogen, chlorine or bromine;
R 4 including electron withdrawing groups;
R 1 is located in indoline [2,1-a]The C8, C9, C10 or C11 position of the isoquinoline derivative;
R 2 or R 3 Is located in indoline [2,1-a]At C2 or C3 position of isoquinoline derivative, R 2 Or R 3 May be the same or different.
2. The indoline [2,1-a ] isoquinoline derivative of claim 1 wherein,
the R is 1 The alkyl group of (A) includes C1-C8 alkyl groups, and the R group 1 The alkoxy group of (A) includes C1-C8 alkoxy groups;
said R is 2 The aryl group includes phenyl or a plurality of aryl groups containing a push-pull electron group, R 2 The alkoxy group of (b) includes a C1-C8 alkoxy group;
the R is 3 The aryl group of (A) includes phenyl or a plurality of aryl groups containing a pull-electron group, R 3 The alkoxy group of (A) includes C1-C8 alkoxy groups;
the R is 4 The electron-withdrawing group of (a) includes a cyano group or a C1-C8 alkyl ester group.
3. The indoline [2,1-a ] isoquinoline derivative of claim 1 wherein,
the R is 1 The C1-C8 alkyl group of (A) includes t-butyl, methyl, ethyl, isopropyl or n-butyl, and the R is 1 The C1-C8 alkoxy group of (1) includes methoxy or ethoxy;
the R is 2 The C1-C8 alkoxy group of (1) includes methoxy or ethoxy;
the R is 3 The C1-C8 alkoxy group of (1) includes a methoxy group or an ethoxy group.
4. The indoline [2,1-a ] isoquinoline derivative of claim 1 wherein the indoline [2,1-a ] isoquinoline derivative is selected from the group consisting of:
5. a method for preparing indoline [2,1-a ] isoquinoline derivatives, comprising:
n-aryl tetrahydroisoquinoline and organic nitrile are taken as raw materials, and a photoelectrocatalysis reaction is adopted at room temperature to obtain the indoline [2,1-a ] isoquinoline derivative; the reaction formula of the synthesis process is as follows:
wherein, the indoline [2,1-a ] isoquinoline derivative is a compound 4;
R 1 including alkyl, alkoxy, hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano;
R 2 including aryl, alkoxy, hydrogen, chlorine or bromine;
R 3 including aryl, alkoxy, hydrogen, chlorine or bromine;
R 4 including electron withdrawing groups;
R 1 is located in indoline [2,1-a ]]The C8, C9, C10 or C11 position of the isoquinoline derivative;
R 2 or R 3 Is located in indoline [2,1-a]At C2 or C3 position of isoquinoline derivative, R 2 Or R 3 May be the same or different.
6. Indoline [2,1-a according to claim 5]The preparation method of the isoquinoline derivative is characterized in that the photoelectrocatalysis comprises photocatalysis and electrocatalysis, and the photocatalysis adopts visible light catalysis; the electrocatalytic unbiased electrode pair, the anode of which comprises BiVO 4 Photoanode or BiVO 4 The composite photo-anode of (2).
7. Indoline [2,1-a according to claim 5]A process for the preparation of isoquinoline derivatives, characterized in that the BiVO is 4 The compound comprises BiVO 4 And is located in the BiVO 4 FTO, ITO or conductive ceramic layer on the surface.
8. Indoline [2,1-a according to claim 5]A process for producing an isoquinoline derivative, wherein the electrolyte for the photoelectrocatalytic reaction comprises Et 4 NBr、Et 4 NCl、n-Bu 4 NBr、n-Bu 4 NCl, KCl or NH 4 Any one or a mixture of more of Cl.
9. The method for preparing indoline [2,1-a ] isoquinoline derivative according to claim 6 wherein the visible light catalyzed light source comprises white light or monochromatic light; the reaction time is 4-12 hours, and the solvent of the reaction comprises alcohol.
10. A compound for use in medicine, comprising the indoline [2,1-a ] isoquinoline derivative of any one of claims 1 to 4.
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| CN112979644A (en) * | 2021-02-19 | 2021-06-18 | 南京工业大学 | Method for preparing fluoromethylation indole [2,1, a ] isoquinoline derivative by using photocatalysis microchannel |
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| CN112979644A (en) * | 2021-02-19 | 2021-06-18 | 南京工业大学 | Method for preparing fluoromethylation indole [2,1, a ] isoquinoline derivative by using photocatalysis microchannel |
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