CN111910206A - Method for synthesizing 3-cyano-substituted imidazo [1,5-a ] quinoline compound - Google Patents
Method for synthesizing 3-cyano-substituted imidazo [1,5-a ] quinoline compound Download PDFInfo
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- CN111910206A CN111910206A CN201910376115.3A CN201910376115A CN111910206A CN 111910206 A CN111910206 A CN 111910206A CN 201910376115 A CN201910376115 A CN 201910376115A CN 111910206 A CN111910206 A CN 111910206A
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- -1 3-cyano-substituted imidazo [1,5-a ] quinoline compound Chemical class 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 30
- 230000002194 synthesizing effect Effects 0.000 title abstract description 9
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical class C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 claims abstract description 61
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 19
- 238000003756 stirring Methods 0.000 claims abstract description 18
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003792 electrolyte Substances 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 238000010490 three component reaction Methods 0.000 claims abstract description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 28
- 229910052697 platinum Inorganic materials 0.000 claims description 14
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 claims description 12
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 12
- 229940107816 ammonium iodide Drugs 0.000 claims description 12
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052759 nickel Inorganic materials 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 239000007772 electrode material Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 claims description 2
- 229910001486 lithium perchlorate Inorganic materials 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
- RXMRGBVLCSYIBO-UHFFFAOYSA-M tetramethylazanium;iodide Chemical compound [I-].C[N+](C)(C)C RXMRGBVLCSYIBO-UHFFFAOYSA-M 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 239000003054 catalyst Substances 0.000 claims 1
- SQQXRXKYTKFFSM-UHFFFAOYSA-N chembl1992147 Chemical class OC1=C(OC)C(OC)=CC=C1C1=C(C)C(C(O)=O)=NC(C=2N=C3C4=NC(C)(C)N=C4C(OC)=C(O)C3=CC=2)=C1N SQQXRXKYTKFFSM-UHFFFAOYSA-N 0.000 claims 1
- 229940124669 imidazoquinoline Drugs 0.000 claims 1
- OWZFYIIJHLFOIG-UHFFFAOYSA-N imidazo[1,5-a]quinoline Chemical class C1=CC=C2N3C=NC=C3C=CC2=C1 OWZFYIIJHLFOIG-UHFFFAOYSA-N 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 21
- 238000001228 spectrum Methods 0.000 description 21
- 238000007333 cyanation reaction Methods 0.000 description 17
- 239000003480 eluent Substances 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 238000012512 characterization method Methods 0.000 description 10
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 238000004983 proton decoupled 13C NMR spectroscopy Methods 0.000 description 10
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YHECNVQRKTVXHF-UHFFFAOYSA-N 1-[4-(trifluoromethyl)phenyl]imidazo[1,5-a]quinoline-3-carbonitrile Chemical compound C1=CC=C2C(=C1)C=CC3=C(N=C(N32)C4=CC=C(C=C4)C(F)(F)F)C#N YHECNVQRKTVXHF-UHFFFAOYSA-N 0.000 description 2
- XQIIMAXDGKSPPP-UHFFFAOYSA-N 1-phenylimidazo[1,5-a]quinoline-3-carbonitrile Chemical compound C1=CC=C(C=C1)C2=NC(=C3N2C4=CC=CC=C4C=C3)C#N XQIIMAXDGKSPPP-UHFFFAOYSA-N 0.000 description 2
- JJPSZKIOGBRMHK-UHFFFAOYSA-N 2,6-dimethylquinoline Chemical compound N1=C(C)C=CC2=CC(C)=CC=C21 JJPSZKIOGBRMHK-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005868 electrolysis reaction Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- PXJACNDVRNAFHD-UHFFFAOYSA-N (2-methoxyphenyl)methanamine Chemical compound COC1=CC=CC=C1CN PXJACNDVRNAFHD-UHFFFAOYSA-N 0.000 description 1
- BJFPYGGTDAYECS-UHFFFAOYSA-N (3-chlorophenyl)methanamine Chemical compound NCC1=CC=CC(Cl)=C1 BJFPYGGTDAYECS-UHFFFAOYSA-N 0.000 description 1
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 description 1
- RGXUCUWVGKLACF-UHFFFAOYSA-N (3-methylphenyl)methanamine Chemical compound CC1=CC=CC(CN)=C1 RGXUCUWVGKLACF-UHFFFAOYSA-N 0.000 description 1
- YMVFJGSXZNNUDW-UHFFFAOYSA-N (4-chlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1 YMVFJGSXZNNUDW-UHFFFAOYSA-N 0.000 description 1
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical compound CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- YKNZTUQUXUXTLE-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=CC(C(F)(F)F)=C1 YKNZTUQUXUXTLE-UHFFFAOYSA-N 0.000 description 1
- PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000002848 electrochemical method Methods 0.000 description 1
- 230000005518 electrochemistry Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Electrochemistry (AREA)
- Materials Engineering (AREA)
- Metallurgy (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a method for synthesizing a 3-cyano-substituted imidazo [1,5-a ] quinoline compound. In particular, the present invention provides a method for constructing 3-cyano substituted imidazo [1,5-a ] quinolines using an electrocatalytic three-component reaction, said method comprising the steps of: 1) respectively adding electrolyte, unsubstituted or substituted 2-methylquinoline, substituted aliphatic amine, a cyano source and a solvent into a non-separated electrolytic tank, installing electrodes into the electrolytic tank, and electrifying and stirring for reaction; 2) and separating and purifying the solution after the reaction is finished to obtain the 3-cyano-substituted imidazo [1,5-a ] quinoline compound.
Description
Technical Field
The invention belongs to the field of organic synthesis methodology, and particularly relates to a method for synthesizing a 3-cyano-substituted imidazo [1,5-a ] quinoline compound.
Background
Aryl cyanide compounds are widely found in natural products, drug molecules, pesticides and dyes.[1]In addition, since a cyano group can be converted into a wide variety of functional groups, it is a very important synthetic intermediate in organic chemistry.[2]Therefore, the synthesis of aryl cyanide compounds has been the focus of research of organic chemists,[3]in particular cyano-functionalized imidazo [1,5-a ]]A nitrogen-containing heterocyclic ring,[4]it is an important aromatic cyano compound with a bioactive framework and is less studied than other aryl cyano compounds.
In recent years, some metal-catalyzed cyano-functionalized imidazo [1,5-a ] s have been developed at home and abroad]A nitrogen-containing heterocycle.[5]However, metalOften affects the utility of the synthesized drug and functional molecules and requires multiple steps to remove, which is cumbersome and results in large amounts of waste liquid to be discharged.
Organic electrochemistry is used as a green synthesis means, and the use of metal and chemical oxidants in the prior art can be avoided or reduced.[6]Recently, there are also some methods for synthesizing cyano compounds by electrochemical methods.[7]However, there is no report on the construction of aromatic cyano compounds for multicomponent reactions.
In the invention, the 3-cyano-substituted imidazoquinoline [1,5-a ] compound is synthesized by using unsubstituted or substituted 2-methylquinoline, substituted aliphatic amine and a cyano source in a one-pot method under electrochemical conditions, and the use of metal and chemical oxidants is not needed, so that the atom economy is high, and the reaction is green.
Disclosure of Invention
The invention develops a method for synthesizing a 3-cyano-substituted imidazo [1,5-a ] quinoline compound.
Specifically, the present invention includes the following aspects:
the invention provides a method for constructing a 3-cyano-substituted imidazo [1,5-a ] quinoline compound by utilizing an electrocatalytic three-component reaction, which comprises the following steps:
1) respectively adding electrolyte, unsubstituted or substituted 2-methylquinoline, substituted aliphatic amine, a cyano source and a solvent into a non-separated electrolytic tank, installing electrodes into the electrolytic tank, and electrifying and stirring for reaction;
2) and separating and purifying the solution after the reaction is finished to obtain the 3-cyano-substituted imidazo [1,5-a ] quinoline compound.
The term "undivided electrolysis cell" refers to a single-port electrolysis cell in which both the anode and the cathode are placed in a single reaction cell.
The invention provides a method for synthesizing a 3-cyano-substituted imidazo [1,5-a ] quinoline compound, which comprises the following steps:
1) adding an electrolyte, 2-methylquinoline of formula (I), aliphatic amine of formula (II), cyano source of formula (III) and solvent into a reactor, respectively, installing electrodes into the reactor, and stirring for reaction.
R3-CN formula (III)
Preferably, the electrode is selected from conventional electrodes such as platinum electrodes, carbon electrodes, nickel electrodes, copper electrodes, and the like. More preferably, the 2-methylquinoline is selected from the following structures:
wherein R is1Selected from hydrogen, C1-C8Alkyl, substituted C1-C8Alkyl, halogen, C6-C15Aryl and substituted C6-C15And (4) an aryl group.
More preferably, the fatty amine is selected from the following structures:
wherein R is2Is selected from C1-C8Alkyl, substituted C1-C8Alkyl radical, C4-C15Aryl and substituted C4-C15And (4) an aryl group.
More preferably, the cyano source is selected from the following structures:
R3-CN
formula (III)
Wherein R is3Is selected from C1-C8Alkyl, substituted C1-C8Alkyl groups and trimethylsilyl groups.
Preferably, substituted C1-C8Alkyl, substituted C6-C15Aryl and substituted C4-C15Substituents in aryl groups being selected from C1-C6Alkyl, halogen, halogeno C1-C6Alkyl radical, C1-C6Alkoxy, and the like.
Preferably, R1Selected from H, methyl, etc.
Preferably, R2Selected from phenyl, p-methylphenyl, p-chlorophenyl, p-trifluoromethylphenyl, m-methylphenyl, m-fluorophenyl, m-chlorophenyl, m-trifluoromethylphenyl, o-methoxyphenyl, etc.
Preferably, R3Selected from methyl, ethyl, benzyl, trimethylsilyl and the like.
Preferably, the solvent is selected from the group consisting of dimethylsulfoxide, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide, acetonitrile, water and 1, 2-dichloroethane.
Preferably, the electrolyte is selected from tetrabutylammonium tetrafluoroborate, lithium perchlorate, ammonium acetate, ammonium tetrafluoroborate, ammonium hexafluorophosphate, ammonium iodide, potassium iodide, sodium iodide, tetramethylammonium iodide and tetrabutylammonium iodide.
Preferably, the molar ratio of the electrolyte to the unsubstituted or substituted 2-methylquinoline is 0.8 to 1.2.
Preferably, the molar ratio of the unsubstituted or substituted 2-methylquinoline to the substituted fatty amine is 1:1 to 1: 4.
Preferably, the molar ratio of the unsubstituted or substituted 2-methylquinoline to the cyano source is 1:1 to 1: 4.
Preferably, the starting concentration of unsubstituted or substituted 2-methylquinoline is from 0.1 to 0.3 mol/L.
Preferably, the temperature of the stirring reaction is 0-100 ℃.
Preferably, the electrode is selected from the group consisting of a platinum electrode, a carbon electrode, a nickel electrode and a copper electrode.
The method further comprises the steps of:
2) separating and purifying the solution after the reaction is finished to obtain the 3-cyano-substituted imidazo [1,5-a ] quinoline compound:
wherein R is1、R2The inverse of the anterior aspectThe substituents of the compound are determined.
Preferably, the separation and purification modes comprise column chromatography, liquid chromatography, distillation, recrystallization and other separation modes;
more preferably, the separation and purification mode is column chromatography.
Preferably, the eluent for the column chromatography is petroleum ether/ethyl acetate. This is not to say that other eluent systems are not a requirement of the present application, as long as reagents meeting the purpose of elution can be used.
Specifically, the cyanation product of the present invention may be a compound having the following general formula:
by the method, 3-cyano-substituted imidazo [1,5-a ] quinoline compounds can be constructed in one pot, so that a plurality of important pharmaceutical intermediates can be derived. The invention develops a synthetic method of a 3-cyano-substituted imidazo [1,5-a ] quinoline compound.
Drawings
FIG. 1 shows the results obtained in example 11H NMR；
FIG. 2 shows the results obtained in example 113C NMR；
FIG. 3 shows the results obtained in example 21H NMR；
FIG. 4 shows the results obtained in example 213C NMR；
FIG. 5 shows the results obtained in example 31H NMR；
FIG. 6 shows the results obtained in example 313C NMR；
FIG. 7 shows the results obtained in example 41H NMR；
FIG. 8 shows the results obtained in example 413C NMR；
FIG. 9 shows the results obtained in example 513C NMR；
FIG. 10 shows the results obtained in example 51H NMR；
FIG. 11 shows the results obtained in example 613C NMR；
FIG. 12 shows the results obtained in example 613C NMR；
FIG. 13 shows the results obtained in example 71H NMR；
FIG. 14 shows the results obtained in example 713C NMR；
FIG. 15 shows the results obtained in example 81H NMR；
FIG. 16 shows the results obtained in example 813C NMR；
FIG. 17 shows the results obtained in example 91H NMR；
FIG. 18 shows the results obtained in example 913C NMR；
FIG. 19 shows the results obtained in example 101H NMR；
FIG. 20 shows the results obtained in example 1013C NMR。
Detailed Description
Reference will now be made in detail to the embodiments of the present invention, the nuclear magnetic spectra of which are illustrated in the accompanying drawings.
A method for synthesizing 3-cyano substituted imidazo [1,5-a ] quinolines, comprising the following steps:
1) respectively adding electrolyte, unsubstituted or substituted 2-methylquinoline, substituted aliphatic amine, a cyano source and a solvent into a non-separated electrolytic tank, installing electrodes into the electrolytic tank, and electrifying and stirring for reaction;
specifically, in a 10mL non-separated electrolytic tank, adding unsubstituted or substituted 2-methylquinoline, substituted aliphatic amine, a cyano source and a solvent into the non-separated electrolytic tank respectively, installing electrodes into the electrolytic tank, and electrifying and stirring for reaction; the molar ratio of the electrolyte to the unsubstituted or substituted 2-methylquinoline is 0.8-1.2. The mol ratio of the unsubstituted or substituted 2-methylquinoline to the substituted aliphatic amine is 1: 1-1: 4; the molar ratio of the cyanide source to the cyanide source is 1:1 to 1: 4. The initial concentration of the unsubstituted or substituted 2-methylquinoline is 0.1-0.3mol/L, and the stirring reaction temperature is 0-100 ℃. The electrode material is selected from conventional commercially available electrode materials, such as platinum electrodes, carbon electrodes, nickel electrodes, copper electrodes, and the like.
2) And separating and purifying the solution after the reaction is finished to obtain the 3-cyano-substituted imidazo [1,5-a ] quinoline compound.
Specifically, the solution after completion of the reaction was spin-dried under reduced pressure, and the residue was separated by silica gel column chromatography and passed through a column using petroleum ether/ethyl acetate system as an eluent. This is not to say that other eluent systems are not a requirement of the present application, as long as reagents meeting the purpose of elution can be used.
The reaction formula is as follows:
the application realizes that the 3-cyano-substituted imidazo [1,5-a ] quinoline compound is obtained by the reaction of three components, namely unsubstituted or substituted 2-methylquinoline, substituted aliphatic amine and a cyano source, with high selectivity under electrochemical conditions. The method is a green and efficient method for synthesizing the 3-cyano-substituted imidazo [1,5-a ] quinoline compound.
The following are specific examples of the present application in which unsubstituted or substituted 2-methylquinolines were used as synthesized according to literature procedures[8]. All reagents were purchased from jiuding chemistry, which was a directly purchased analytical pure reagent, without further treatment prior to use. The solvent or eluent is purchased from Chinese medicine.
Example 1:
preparation of 1-phenyl-imidazo [1,5-a ] quinoline-3-carbonitrile
In a 10mL undivided electrolytic cell, 2-methylquinoline (0.3mmol,43.0mg), benzylamine (0.9mmol,96.4mg), trimethylsilyl chloride (0.9mmol,89.3mg), ammonium iodide (0.3mmol,43.5mg) and N, N-dimethylacetamide (3.0mL) were placed, and the reaction was carried out with energization at 90 ℃ while using a platinum sheet electrode as both the anode and the cathode (I ═ 10 mA). After completion of the reaction (TLC follow-up), the residue obtained by spin-drying was chromatographed on a column using ethyl acetate/petroleum ether system as eluent to give the product 1-phenyl-imidazo [1,5-a ] quinoline-3-carbonitrile in 97% yield.
The cyanation product was analyzed by a nuclear magnetic resonance spectrometer, and the results are shown in fig. 1-2. FIG. 1 is a drawing showing a cyanation product provided in example 1 of the present invention1H nuclear magnetic resonance (1H-NMR) spectrum; FIG. 2 is a drawing showing the cyanation product provided in example 1 of the present invention13C nuclear magnetic resonance (13C-NMR) spectrum.
The product is measured and the characterization data is1H NMR(DMSO-d6,400MHz, ppm):＝8.00–7.98(m,1H),7.73(s,2H),7.70-7.66(m,3H),7.65-7.61 (m,2H),7.55-7.51(m,1H),7.43-7.39(m,1H),7.34(d,J＝8.0Hz,1H)；13C{1H}NMR(DMSO-d6,100MHz,ppm):＝143.5,137.0,132.2,131.7, 130.6,129.9,129.9,129.3,129.3,127.9,126.7,125.1,116.9,115.5,114.5, 104.1。
Example 2:
preparation of 1- (4-methylphenyl) -imidazo [1,5-a ] quinoline-3-carbonitrile
In a 10mL undivided electrolytic cell, 2-methylquinoline (0.3mmol,43.0mg), 4-methylbenzylamine (0.9mmol,109.1mg), trimethylsilyl chloride (0.9mmol,89.3mg), ammonium iodide (0.3mmol,43.5mg) and N, N-dimethylacetamide (3.0mL) were placed, and a platinum sheet electrode was used as both an anode and a cathode, and the reaction was carried out under energization at 90 ℃ with stirring (I ═ 10 mA). After completion of the reaction (TLC follow-up), the residue obtained by spin-drying was chromatographed on a column using ethyl acetate/petroleum ether system as eluent to give the product 1- (4-methylphenyl) -imidazo [1,5-a ] quinoline-3-carbonitrile in 94% yield.
The cyanation product was analyzed by a nuclear magnetic resonance spectrometer, and the results are shown in fig. 3-4. FIG. 3 is a drawing showing the cyanation product provided in example 2 of the present invention1H nuclear magnetic resonance (1H-NMR) spectrum; FIG. 4 provides examples 2 of the present inventionOf the cyanation product of (a)13C nuclear magnetic resonance (13C-NMR) spectrum.
The product is measured and the characterization data is1H NMR(CDCl3,400MHz,ppm): ＝7.75-7.73(m,1H),7.58-7.53(m,2H),7.51-7.48(m,2H),7.46-7.40 (m,2H),7.37-7.35(m,2H),7.33-7.29(m,1H),2.49(s,3H)；13C{1H}NMR (CDCl3,100MHz,ppm):＝143.9,140.6,137.1,132.1,129.8,129.5,129.3, 129.0,128.9,126.9,126.4,125.2,117.5,115.1,114.7,105.6,21.6。
Example 3:
preparation of 1- (4-chlorophenyl) imidazo [1,5-a ] quinoline-3-carbonitrile
In a 10mL undivided electrolytic cell, 2-methylquinoline (0.3mmol,43.0mg), 4-chlorobenzylamine (0.9mmol,127.4mg), trimethylsilyl chloride (0.9mmol,89.3mg), ammonium iodide (0.3mmol,43.5mg) and N, N-dimethylacetamide (3.0mL) were placed, and a platinum sheet electrode was used as both an anode and a cathode, and the reaction was carried out under energization at 90 ℃ with stirring (I ═ 10 mA). After completion of the reaction (TLC follow-up), the residue obtained by spin-drying was chromatographed on a column using ethyl acetate/petroleum ether system as eluent to give the product 1- (4-chlorophenyl) imidazo [1,5-a ] quinoline-3-carbonitrile in 79% yield.
The cyanation product was analyzed by a nuclear magnetic resonance spectrometer, and the results are shown in fig. 5 to 6. FIG. 5 is a cyanoated product provided in example 3 of the present invention1H nuclear magnetic resonance (1H-NMR) spectrum; FIG. 6 is a cyanoated product provided in example 3 of the present invention13C nuclear magnetic resonance (13C-NMR) spectrum.
The product is measured and the characterization data is1H NMR(CDCl3,400MHz,ppm): ＝7.79-7.77(m,1H),7.61-7.54(m,6H),7.50-7.44(m,2H),7.39-7.34 (m,1H)；13C{1H}NMR(CDCl3,100MHz,ppm):＝142.4,137.3,136.6, 131.9,131.1,130.4,129.5,129.5,129.1,127.1,126.6,125.3,117.3,114.8, 114.8,106.1。
Example 4:
preparation of 1- (4-trifluoromethylphenyl) imidazo [1,5-a ] quinoline-3-carbonitrile
In a 10mL undivided electrolytic cell, 2-methylquinoline (0.3mmol,43.0mg), 4-trifluoromethylbenzylamine (0.9mmol,157.6mg), trimethylsilyl chloride (0.9mmol,89.3mg), ammonium iodide (0.3mmol,43.5mg) and N, N-dimethylacetamide (3.0mL) were placed, and a platinum sheet electrode was used as both an anode and a cathode, and the reaction was carried out under energization at 90 ℃ with stirring (I ═ 10 mA). After completion of the reaction (TLC follow-up), the residue obtained by spin-drying was chromatographed on a column using ethyl acetate/petroleum ether system as eluent to give the product 1- (4-trifluoromethylphenyl) imidazo [1,5-a ] quinoline-3-carbonitrile in 89% yield.
The cyanation product was analyzed by a nuclear magnetic resonance spectrometer, and the results are shown in fig. 7 to 8. FIG. 7 is a cyanoated product provided in example 4 of the present invention1H nuclear magnetic resonance (1H-NMR) spectrum; FIG. 8 is a cyanoated product provided in example 4 of the present invention13C nuclear magnetic resonance (13C-NMR) spectrum.
The product is measured and the characterization data is1H NMR(CDCl3,400MHz,ppm): ＝7.85-7.79(m,5H),7.60(d,J＝9.3Hz,1H),7.53-7.48(m,3H),7.40- 7.36(m,1H)；13C{1H}NMR(CDCl3,100MHz,ppm):＝141.9,137.4,135.6, 132.3(q,J＝32.7Hz),131.7,130.2,129.6,129.2,127.4,126.8,126.1(q,J＝ 3.8Hz),125.3,123.7(q,J＝271.1Hz),117.3,114.7,114.7,106.4。
Example 5:
preparation of 1- (3-methylphenyl) imidazo [1,5-a ] quinoline-3-carbonitrile
In a 10mL undivided electrolytic cell, 2-methylquinoline (0.3mmol,43.0mg), 3-methylbenzylamine (0.9mmol,109.1mg), trimethylsilyl chloride (0.9mmol,89.3mg), ammonium iodide (0.3mmol,43.5mg) and N, N-dimethylacetamide (3.0mL) were placed, and a platinum sheet electrode was used as both an anode and a cathode, and the reaction was carried out under energization at 90 ℃ with stirring (I ═ 10 mA). After completion of the reaction (TLC follow-up), the residue obtained by spin-drying was chromatographed on a column using ethyl acetate/petroleum ether system as eluent to give the product 1- (3-methylphenyl) imidazo [1,5-a ] quinoline-3-carbonitrile in 75% yield.
The cyanation product was analyzed by a nuclear magnetic resonance spectrometer, and the results are shown in fig. 9-10. FIG. 9 is a cyanoated product provided in example 5 of the present invention1H nuclear magnetic resonance (1H-NMR) spectrum; FIG. 10 is a cyanoated product provided in example 5 of the present invention13C nuclear magnetic resonance (13C-NMR) spectrum.
The product is measured and the characterization data is1H NMR(CDCl3,400MHz,ppm): ＝7.76-7.74(m,1H),7.57-7.54(m,2H),7.47-7.37(m,6H),7.33-7.29 (m,1H),2.44(s,3H)；13C{1H}NMR(CDCl3,100MHz,ppm):＝143.8,139.2, 137.1,132.1,131.9,131.1,130.2,129.3,129.0,126.9,126.6,126.4,125.2, 117.5,115.1,114.7,105.7,21.5。
Example 6:
preparation of 1- (3-fluorophenyl) imidazo [1,5-a ] quinoline-3-carbonitrile
In a 10mL undivided electrolytic cell, 2-methylquinoline (0.3mmol,43.0mg), 3-fluorobenzylamine (0.9mmol,112.6mg), trimethylsilyl chloride (0.9mmol,89.3mg), ammonium iodide (0.3mmol,43.5mg) and N, N-dimethylacetamide (3.0mL) were placed, and a platinum sheet electrode was used as both an anode and a cathode, and the reaction was carried out under energization at 90 ℃ with stirring (I ═ 10 mA). After completion of the reaction (TLC follow-up), the residue obtained by spin-drying was chromatographed on a column using ethyl acetate/petroleum ether system as eluent to give the product 1- (3-fluorophenyl) imidazo [1,5-a ] quinoline-3-carbonitrile in 88% yield.
The cyanation product was analyzed by a nuclear magnetic resonance spectrometer, and the results are shown in fig. 11 to 12. FIG. 11 is a cyanoated product provided in example 6 of the present invention1H nuclear magnetic resonance (1H-NMR) spectrum; FIG. 12 is a drawing showing the cyanation product provided in example 6 of the present invention13C nuclear magnetic resonance (13C-NMR) spectrum.
The product is measured and the characterization data is1H NMR(CDCl3,400MHz,ppm): ＝7.80-7.77(m,1H),7.60-7.53(m,3H),7.50-7.45(m,2H),7.44-7.41 (m,1H),7.38-7.29(m,3H)；13C{1H}NMR(CDCl3,100MHz,ppm):＝ 162.8(d,J＝247.4Hz),142.1(d,J＝2.5Hz),137.2,133.9(d,J＝8.1Hz), 131.8,130.9(d,J＝8.5Hz),129.5,129.2,127.2,126.7,125.5(d,J＝3.3Hz), 125.2,117.6(d,J＝20.7Hz),117.3,117.0(d,J＝22.7Hz),114.8,114.7, 106.0。
Example 7:
preparation of 1- (3-chlorophenyl) imidazo [1,5-a ] quinoline-3-carbonitrile
In a 10mL undivided electrolytic cell, 2-methylquinoline (0.3mmol,43.0mg), 3-chlorobenzylamine (0.9mmol,127.4mg), trimethylsilyl chloride (0.9mmol,89.3mg), ammonium iodide (0.3mmol,43.5mg) and N, N-dimethylacetamide (3.0mL) were placed, and a platinum sheet electrode was used as both an anode and a cathode, and the reaction was carried out under energization at 90 ℃ with stirring (I ═ 10 mA). After completion of the reaction (TLC follow-up), the residue obtained by spin-drying was chromatographed on a column using ethyl acetate/petroleum ether system as eluent to give the product 1- (3-chlorophenyl) imidazo [1,5-a ] quinoline-3-carbonitrile in 90% yield.
The cyanation product was analyzed by a nuclear magnetic resonance spectrometer, and the results are shown in fig. 13 to 14. FIG. 13 is a cyanoated product of example 7 of the present invention1H nuclear magnetic resonance (1H-NMR) spectrum; FIG. 14 is a drawing of a cyanation product provided in example 7 of this invention13C nuclear magnetic resonance (13C-NMR) spectrum.
The product is measured and the characterization data is1H NMR(CDCl3,400MHz,ppm): ＝7.79-7.77(m,1H),7.65-7.64(m,1H),7.59-7.45(m,7H),7.39-7.34 (m,1H)；13C{1H}NMR(CDCl3,100MHz,ppm):＝142.0,137.2,135.1, 133.6,131.8,130.6,130.4,129.8,129.6,129.2,127.8,127.3,126.7,125.2, 117.3,114.8,114.7,106.0。
Example 8:
preparation of 1- (3-trifluoromethylphenyl) imidazo [1,5-a ] quinoline-3-carbonitrile
In a 10mL undivided electrolytic cell, 2-methylquinoline (0.3mmol,43.0mg), 3-trifluoromethylbenzylamine (0.9mmol,157.6mg), trimethylsilyl chloride (0.9mmol,89.3mg), ammonium iodide (0.3mmol,43.5mg) and N, N-dimethylacetamide (3.0mL) were placed, and a platinum sheet electrode was used as both an anode and a cathode, and the reaction was carried out under energization at 90 ℃ with stirring (I ═ 10 mA). After completion of the reaction (TLC follow-up), the residue obtained by spin-drying was chromatographed on a column using ethyl acetate/petroleum ether system as eluent to give the product 1- (3-trifluoromethylphenyl) imidazo [1,5-a ] quinoline-3-carbonitrile in 84% yield.
The cyanation product was analyzed by a nuclear magnetic resonance spectrometer, and the results are shown in fig. 15 to 16. FIG. 15 is a cyanoated product provided in example 8 of the present invention1H nuclear magnetic resonance (1H-NMR) spectrum; FIG. 16 is a cyanoated product provided in example 8 of the present invention13C nuclear magnetic resonance (13C-NMR) spectrum.
The product is measured and the characterization data is1H NMR(CDCl3,400MHz,ppm): ＝7.95(s,1H),7.88-7.85(m,2H),7.82-7.80(m,1H),7.74-7.70(m,1H), 7.60(d,J＝9.4Hz,1H),7.52-7.47(m,3H),7.38-7.33(m,1H)；13C{1H}NMR(CDCl3,100MHz,ppm):＝141.8,137.4,133.0,132.8,131.7 (q,J＝32.9Hz),131.7,129.7,129.7,127.4,127.1(q,J＝3.7Hz),126.8,126.7 (q,J＝3.7Hz),125.3,123.6(q,J＝271.2Hz),122.1,117.2,114.7,114.7, 106.3。
Example 9:
preparation of 1- (2-methoxyphenyl) imidazo [1,5-a ] quinoline-3-carbonitrile
In a 10mL undivided electrolytic cell, 2-methylquinoline (0.3mmol,43.0mg), 2-methoxybenzylamine (0.9mmol,123.5mg), trimethylsilyl chloride (0.9mmol,89.3mg), ammonium iodide (0.3mmol,43.5mg) and N, N-dimethylacetamide (3.0mL) were placed, and a platinum sheet electrode was used as both an anode and a cathode, and the reaction was carried out under energization at 90 ℃ with stirring (I ═ 10 mA). After completion of the reaction (TLC follow-up), the residue obtained by spin-drying was chromatographed on a column using ethyl acetate/petroleum ether system as eluent to give the product 1- (2-methoxyphenyl) imidazo [1,5-a ] quinoline-3-carbonitrile in 85% yield.
The cyanation product was analyzed by a nuclear magnetic resonance spectrometer, and the results are shown in fig. 17 to 18. FIG. 17 is a drawing of a cyanation product provided in example 9 of this invention1H nuclear magnetic resonance (1H-NMR) spectrum; FIG. 18 is a cyanoated product of example 9 of the present invention13C nuclear magnetic resonance (13C-NMR) spectrum.
The product is measured and the characterization data is1H NMR(CDCl3,400MHz,ppm): ＝7.76-7.73(m,1H),7.62-7.56(m,3H),7.49(d,J＝8.6Hz,1H),7.46- 7.42(m,2H),7.32-7.28(m,1H),7.19-7.15(m,1H),7.04(d,J＝8.3Hz, 1H),3.59(s,3H)；13C{1H}NMR(CDCl3,100MHz,ppm):＝158.1,141.0, 137.0,132.6,132.2,131.8,129.0,126.8,126.2,124.9,121.5,121.3,116.5, 115.2,114.8,111.1,105.5,55.4。
Example 10:
preparation of 1-phenyl-7-methylimidazo [1,5-a ] quinoline-3-carbonitrile
In a 10mL undivided electrolytic cell, 2, 6-dimethylquinoline (0.3mmol,47.2 mg), benzylamine (0.9mmol,96.4mg), trimethylsilyl chloride (0.9mmol,89.3mg), ammonium iodide (0.3mmol,43.5mg) and N, N-dimethylacetamide (3.0mL) were placed, and a platinum sheet electrode was used as both an anode and a cathode, and the reaction was carried out under energization at 90 ℃ with stirring (I ═ 10 mA). After completion of the reaction (TLC follow-up), the residue obtained by spin-drying was chromatographed on a column using ethyl acetate/petroleum ether system as eluent to give the product 1-phenyl-7-methylimidazo [1,5-a ] quinoline-3-carbonitrile in 95% yield.
The cyanolated product was analyzed by a nuclear magnetic resonance spectrometer and the results are shown in fig. 19-20. FIG. 19 is a cyanoated product provided in example 10 of the present invention1H nuclear magnetic resonance (1H-NMR) spectrum; FIG. 20 is a cyanoated product provided in example 10 of the present invention13C nuclear magnetic resonance (13C-NMR) spectrum.
The product is measured and the characterization data is1H NMR(CDCl3,400MHz,ppm): ＝7.63-7.52(m,7H),7.40-7.36(m,2H),7.13-7.10(m,1H),2.43(s,3H)；13C{1H}NMR(CDCl3,100MHz,ppm):＝143.4,137.1,136.4,132.1,130.3, 130.1,130.0,129.7,129.1,129.1,126.9,125.2,117.2,115.2,114.6,105.6, 20.9。
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
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Claims (10)
1. a method of constructing a 3-cyano substituted imidazo [1,5-a ] quinoline compound using an electrocatalytic three-component reaction, the method comprising the steps of:
1) respectively adding electrolyte, unsubstituted or substituted 2-methylquinoline, substituted aliphatic amine, a cyano source and a solvent into a non-separated electrolytic tank, installing electrodes into the electrolytic tank, and electrifying and stirring for reaction;
2) and separating and purifying the solution after the reaction is finished to obtain the 3-cyano-substituted imidazo [1,5-a ] quinoline compound.
2. The method according to claim 1, wherein the catalyst of the reaction is an electrode material such as platinum electrode, carbon electrode, nickel electrode and copper electrode.
3. The method of claim 1, wherein the unsubstituted or substituted 2-methylquinoline has a structure represented by formula (I):
wherein R is1Selected from hydrogen, C1-C8Alkyl, substituted C1-C8Alkyl, halogen, C6-C15Aryl and substituted C6-C15And (4) an aryl group.
4. The method of claim 1, wherein the substituted aliphatic amine has a structure according to formula (II):
wherein R is2Is selected from C1-C8Alkyl, substituted C1-C8Alkyl radical, C4-C15Aryl and substituted C4-C15And (4) an aryl group.
5. The method of claim 1, wherein the cyano source has a structure represented by formula (III):
R3-CN
formula (III)
Wherein R is3Is selected from C1-C8Alkyl, substituted C1-C8Alkyl and trimethylsilyl of (a).
6. The process according to claim 1, wherein the solvent is selected from the group consisting of dimethylsulfoxide, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide, acetonitrile, water and 1, 2-dichloroethane.
7. The method according to claim 1, wherein the molar ratio of the electrolyte to the unsubstituted or substituted 2-methylquinoline is 0.8 to 1.2, and the electrolyte is selected from the group consisting of tetrabutylammonium tetrafluoroborate, lithium perchlorate, ammonium acetate, ammonium tetrafluoroborate, ammonium hexafluorophosphate, ammonium iodide, potassium iodide, sodium iodide, tetramethylammonium iodide, and tetrabutylammonium iodide.
8. The method according to claim 1, wherein the molar ratio of the unsubstituted or substituted 2-methylquinoline to the substituted aliphatic amine is 1:1 to 1:4, the molar ratio of the unsubstituted or substituted 2-methylquinoline to the cyano source is 1:1 to 1:4, and the initial concentration of the unsubstituted or substituted 2-methylquinoline is 0.1 to 0.3 mol/L.
9. The method according to claim 1, wherein the temperature of the stirring reaction is 0-100 ℃, and preferably, the separation and purification means comprises column chromatography, distillation and recrystallization.
10. The method of claim 1, wherein the 3-cyano substituted imidazoquinoline has a structure represented by formula (IV):
wherein,
R1selected from hydrogen, C1-C8Alkyl, substituted C1-C8Alkyl, halogen, C6-C15Aryl and substituted C6-C15An aryl group; and is
R2Is selected from C1-C8Alkyl, substituted C1-C8Alkyl radical, C4-C15Aryl and substituted C4-C15And (4) an aryl group.
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| CN113930791B (en) * | 2021-10-15 | 2023-11-03 | 阜阳师范大学 | Electric synthesis method of pyrido-bipyrimidine tetraketone compound |
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