CN117603131A - Method for introducing thiophenyl group in meta position of nitrogen of pyridine ring and thiophenyl group-containing pyridine compound - Google Patents
Method for introducing thiophenyl group in meta position of nitrogen of pyridine ring and thiophenyl group-containing pyridine compound Download PDFInfo
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- CN117603131A CN117603131A CN202311133110.0A CN202311133110A CN117603131A CN 117603131 A CN117603131 A CN 117603131A CN 202311133110 A CN202311133110 A CN 202311133110A CN 117603131 A CN117603131 A CN 117603131A
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- -1 pyridine compound Chemical class 0.000 title claims abstract description 94
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 31
- 125000001544 thienyl group Chemical group 0.000 title claims abstract description 28
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 26
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title claims abstract description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- RCHBKQDIZMPNEQ-UHFFFAOYSA-N 2-phenyl-3-sulfanylideneisoindol-1-one Chemical compound S=C1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 RCHBKQDIZMPNEQ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000012434 nucleophilic reagent Substances 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 150000002367 halogens Chemical group 0.000 claims description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 239000012038 nucleophile Substances 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 12
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 9
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 239000011593 sulfur Substances 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 7
- 150000003335 secondary amines Chemical group 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Chemical group 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 239000005453 ketone based solvent Substances 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- VQGHOUODWALEFC-UHFFFAOYSA-N alpha-Phenylpyridine Natural products C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 claims 2
- JVZRCNQLWOELDU-UHFFFAOYSA-N gamma-Phenylpyridine Natural products C1=CC=CC=C1C1=CC=NC=C1 JVZRCNQLWOELDU-UHFFFAOYSA-N 0.000 claims 2
- 238000010499 C–H functionalization reaction Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000004576 sand Substances 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- NMHKBABHRKQHOL-UHFFFAOYSA-N 2-phenylsulfanylisoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1SC1=CC=CC=C1 NMHKBABHRKQHOL-UHFFFAOYSA-N 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- IVCJSRREUGDLGG-UHFFFAOYSA-N 3-methyl-5-thiophen-2-ylpyridine Chemical compound CC1=CN=CC(C=2SC=CC=2)=C1 IVCJSRREUGDLGG-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000000975 bioactive effect Effects 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 2
- HJKGBRPNSJADMB-UHFFFAOYSA-N 3-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CN=C1 HJKGBRPNSJADMB-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000005486 sulfidation Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- VYDDROKEDAOZTQ-UHFFFAOYSA-N 1-(2,4-dinitrophenyl)-2H-pyridine Chemical class [O-][N+](=O)c1ccc(N2CC=CC=C2)c(c1)[N+]([O-])=O VYDDROKEDAOZTQ-UHFFFAOYSA-N 0.000 description 1
- MCNUBLFKORCVGA-UHFFFAOYSA-N 1-(2,4-dinitrophenyl)pyridin-1-ium Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC=C1[N+]1=CC=CC=C1 MCNUBLFKORCVGA-UHFFFAOYSA-N 0.000 description 1
- UYHMQTNGMUDVIY-UHFFFAOYSA-M 1-(2,4-dinitrophenyl)pyridin-1-ium;chloride Chemical compound [Cl-].[O-][N+](=O)C1=CC([N+](=O)[O-])=CC=C1[N+]1=CC=CC=C1 UYHMQTNGMUDVIY-UHFFFAOYSA-M 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- LBMOJGOXBWNXHS-UHFFFAOYSA-N 3-(furan-2-yl)pyridine Chemical compound C1=COC(C=2C=NC=CC=2)=C1 LBMOJGOXBWNXHS-UHFFFAOYSA-N 0.000 description 1
- XDELKSRGBLWMBA-UHFFFAOYSA-N 3-iodopyridine Chemical compound IC1=CC=CN=C1 XDELKSRGBLWMBA-UHFFFAOYSA-N 0.000 description 1
- ONBQLBVFTYYJJR-UHFFFAOYSA-N 3-phenylsulfanylpyridine Chemical compound C=1C=CN=CC=1SC1=CC=CC=C1 ONBQLBVFTYYJJR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- UQOXCVFYWKHHQG-UHFFFAOYSA-N OBO.C1=CC=NC=C1 Chemical class OBO.C1=CC=NC=C1 UQOXCVFYWKHHQG-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000005748 halopyridines Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010667 large scale reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to the technical field of organic chemical synthesis, in particular to a method for introducing a thiophenyl group into the meta-position of nitrogen of a pyridine ring and a pyridine compound containing the thiophenyl group. The method for introducing a thiophenyl group in the meta position of nitrogen of a pyridine ring comprises: the activated nitrogen-containing heterocyclic compound reacts with N-phenylthio-phthalimide under the action of a nucleophilic reagent to form a target product. Through a C-H activation mode, a sulfophenyl functional group is directly introduced to the meta-position of nitrogen containing pyridine ring, so that the reaction yield is good, the atom economy is good, and the application potential is high.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to a method for introducing a thiophenyl group into the meta-position of nitrogen of a pyridine ring and a pyridine compound containing the thiophenyl group.
Background
Six-membered nitrogen heterocycles are widely found in a variety of drugs, natural compounds, bioactive molecules, agrochemicals, ligands, functional materials, chemical sensors, and the like. In particular, pyridine is the most common nitrogen heterocycle in drugs approved by the U.S. food and drug administration. In addition, regioselective pyridine C-H benzene sulfidation has attracted considerable attention, and phenylthio-substituted pyridine compounds are of great value in biologically and pharmaceutically active molecules (see structural formulas below).
Previously, the most common preparation methods for benzene sulfided pyridine compounds have been the use of pre-functionalized nitrogen-containing heterocycles such as halopyridine, or organometal reagents such as pyridine boronic acid compounds as starting materials, prepared by coupling with thiols in the presence of transition metals, which generally require high temperatures and expensive ligands to avoid sulfide-induced catalyst deactivation. In addition, the thiols used are unstable and have a strong unpleasant smell, which is not suitable for large-scale reactions. It would therefore be very important to develop a mild process for the meta-selective benzene sulfidation of pyridine.
In view of this, the present invention has been made.
Disclosure of Invention
The present invention provides a method for introducing a thiophenyl group in the meta position of nitrogen in a pyridine ring and a thiophenyl group-containing pyridine compound. According to the embodiment of the invention, the thiophenyl functional group is directly introduced into the meta-position of nitrogen containing pyridine ring in a C-H activation mode, so that the reaction yield is good, the atom economy is good, and the application potential is large.
The invention is realized in the following way:
in a first aspect, the present invention provides a method for introducing a thiophenyl group meta to a nitrogen of a pyridine ring, comprising: reacting the activated nitrogen-containing heterocyclic compound with N-phenylthio-phthalimide under the action of a nucleophilic reagent to form a target product;
wherein the activated nitrogen-containing heterocyclic compound is selected from any one of the compounds shown in the following structural formulas:
the structural formula of the N-phenylthio-phthalimide is as follows: />The structural formula of the target product is as follows: />X represents halogen, R represents halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C6-C20 aryl and substituted or unsubstituted C3-C10 aromatic heterocycle, and the nucleophile is selected from secondary amines.
In an alternative embodiment, X represents chloro or bromo.
In alternative embodiments, R is selected from the group consisting of halogen, C1-C10 alkyl, C6-C15 aryl, and C4-C8 aromatic heterocycle;
preferably, R is selected from halogen, C1-C5 alkyl, C6-C10 aryl, and C4-C6 oxaheterocycle;
preferably, R is selected from any one of halogen, C1-C4 alkyl, phenyl and furyl.
In an alternative embodiment, the conditions of the reaction include: the molar ratio of the activated nitrogen-containing heterocyclic compound to the N-phenylthio-phthalimide is 1:1-4, wherein the dosage of the nucleophilic reagent is that the molar ratio of the activated nitrogenous heterocyclic compound is 1:1-2; the reaction temperature is 80-120 ℃ and the reaction time is 10-24 hours.
In an alternative embodiment, the conditions of the reaction include: the molar ratio of the activated nitrogen-containing heterocyclic compound to the N-phenylthio-phthalimide is 1:2, the using amount of the nucleophile is that the molar ratio of the activated nitrogen-containing heterocyclic compound is 1:1, a step of; the reaction temperature was 80℃and the time was 16 hours.
In an alternative embodiment, the step of forming the activated nitrogen-containing heterocyclic compound comprises: reacting a nitrogen-containing heterocyclic compound raw material with 2, 4-dinitrohalogen benzene; the activated nitrogen-containing heterocyclic compound formed has the following structural formula:
x represents halogen, R represents halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C6-C20 aryl, and substituted or unsubstituted C3-C10 aromatic heterocycle.
In an alternative embodiment, the method comprises: mixing the activated nitrogen-containing heterocyclic compound, the N-phenylthio-phthalimide and an organic solvent for reaction.
In an alternative embodiment, the organic solvent is selected from at least one of nitrile solvents, halogen alkane solvents, and ketone solvents;
preferably, the organic solvent is selected from at least one of acetonitrile, acetone and 1, 2-dichloroethane;
more preferably, the organic solvent is selected from acetonitrile.
In an alternative embodiment, the nucleophile is selected from N-dipropylamine or tetrahydropyrrole.
In a second aspect, the present invention provides a pyridine compound containing a sulfur phenyl group, which is prepared by the method for introducing a sulfur phenyl group into the meta position of nitrogen of a pyridine ring according to any one of the previous embodiments, wherein the structural formula of the pyridine compound containing a sulfur phenyl group is as follows:
x represents halogen, R represents halogen, substituted or unsubstituted C1-C20 alkyl, or a salt thereofSubstituted or unsubstituted C6-C20 aryl and substituted or unsubstituted C3-C10 aromatic heterocycle, said nucleophile being selected from secondary amines.
The invention has the following beneficial effects: the activated nitrogen-containing heterocyclic compound is used as a reaction substrate, reacts with N-phenylthio-phthalimide under the action of a nucleophilic reagent, and then phenylthio is introduced into the nitrogen-containing compound to obtain a C-3-phenylthio-substituted nitrogen-containing compound; the reaction has the advantages of good yield, high selectivity and good atom economy. The phenylthio functional group can be found in various drug molecules and pesticide compounds, and the lipophilicity and bioavailability of the bioactive molecules can be greatly enhanced after the phenylthio group is introduced into the nitrogenous heterocyclic compound. Therefore, it is important to develop a method for synthesizing nitrogen-containing heterocyclic compounds containing a phenylthio group with high selectivity.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a nuclear magnetic resonance spectrum of 3-phenyl-5-thiophenylpyridine of example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance spectrum of 3-phenyl-5-thiophenylpyridine of example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance spectrum of 3- (2-furyl) -5-thiophenylpyridine according to example 2 of the present invention;
FIG. 4 is a nuclear magnetic resonance spectrum of 3- (2-furyl) -5-thiophenylpyridine of example 2 of the present invention;
FIG. 5 is a nuclear magnetic resonance spectrum of 3-methyl-5-thiophenylpyridine provided in example 3 of the present invention;
FIG. 6 is a nuclear magnetic resonance spectrum of 3-methyl-5-thiophenylpyridine provided in example 3 of the present invention;
FIG. 7 is a nuclear magnetic resonance spectrum of 3-iodo-5-thiophenylpyridine of example 4 of the invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
In a first aspect, the present invention provides a method for introducing a thiophenyl group meta to a nitrogen of a pyridine ring, comprising:
s1, forming an activated nitrogen-containing heterocyclic compound;
reacting a nitrogen-containing heterocyclic compound raw material with 2, 4-dinitrohalogen benzene; the method comprises the steps of carrying out a first treatment on the surface of the Wherein the nitrogen-containing heterocyclic compound raw material is selected from compounds shown in the following structural formula:the formed activated nitrogen-containing heterocyclic compound has the structural formula: />Wherein X represents halogen, R represents halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C6-C20 aryl and substituted or unsubstituted C3-C10 aromatic heterocycle.
It should be noted that, R in the activated nitrogen-containing heterocyclic compound does not only represent that the pyridine ring in the activated nitrogen-containing heterocyclic compound is monosubstituted (R is 1), and the number of R may be 2, that is, the pyridine ring in the activated nitrogen-containing heterocyclic compound may be disubstituted.
Meanwhile, phenylsulfation of the pyridine derivative occurs at the C-3 position, and therefore, when the number of substituents is plural, at least the C-3 position is in an unsubstituted state, and the other substituted positions may be arbitrary positions.
Further, X represents chlorine or bromine. R is selected from halogen, C1-C10 alkyl, C6-C15 aryl and C4-C8 aromatic heterocycle; preferably, R is selected from halogen, C1-C5 alkyl, C6-C10 aryl, and C4-C6 oxaheterocycle; for example, R is selected from any one of halogen, C1-C4 alkyl, phenyl and furyl.
The alkyl group may be a straight chain alkyl group or a branched chain alkyl group, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. Halogen may be any one of chlorine and bromine.
Further, the molar ratio of the nitrogen-containing heterocyclic compound raw material to the 2, 4-dinitrohalogen benzene is 1:1.8-2.2, the reaction temperature is 65-75 ℃, and the reaction time is 14-20h.
And carrying out conventional post-treatment such as filtering, washing, drying and the like after the reaction. Embodiments of the present invention will not be described in detail.
The raw materials of the nitrogen-containing heterocyclic compound are wide in sources, low in cost and easy to obtain, and the corresponding activated N-2, 4-dinitrophenyl pyridine salt derivative serving as the nitrogen-containing heterocyclic compound can be obtained through one-step 2, 4-dinitrohalogen benzene activation reaction.
According to the embodiment of the invention, the Zincke salt is formed by introducing 2, 4-dinitrophenyl into the raw material of the nitrogen-containing heterocyclic compound, so that the activated nitrogen-containing heterocyclic compound can react, and then the sulfophenyl is introduced into the meta-position of N of pyridine.
S2, introducing a thiophenyl group;
reacting the activated nitrogen-containing heterocyclic compound with N-phenylthio-phthalimide under the action of a nucleophilic reagent to form a target product;
wherein the activated nitrogen-containing heterocyclic compound is selected from any one of the compounds shown in the following structural formulas:
the structural formula of the N-phenylthio-phthalimide is as follows: />The structural formula of the target product is as follows: />X represents halogen, R represents halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C6-C20 aryl and substituted or unsubstituted C3-C10 aromatic heterocycle, and the nucleophile is selected from secondary amines.
Specifically, the activated nitrogen-containing heterocyclic compound, the N-phenylthio-phthalimide and an organic solvent are mixed for reaction.
Wherein the nucleophile is a secondary amine, including, for example, but not limited to, N-dipropylamine or tetrahydropyrrole.
Further, the reaction conditions include: the molar ratio of the activated nitrogen-containing heterocyclic compound to the N-phenylthio-phthalimide is 1:1-4, wherein the dosage of the nucleophilic reagent is that the molar ratio of the activated nitrogenous heterocyclic compound is 1:1-2; the reaction temperature is 80-120 ℃ and the reaction time is 10-24 hours. For example, the molar ratio of the activated nitrogen-containing heterocyclic compound to the N-phenylthio-phthalimide is 1:2, the using amount of the nucleophile is that the molar ratio of the activated nitrogen-containing heterocyclic compound is 1:1, a step of; the reaction temperature was 80℃and the time was 16 hours.
The organic solvent is at least one selected from nitrile solvents, halogen alkane solvents and ketone solvents; preferably, the organic solvent is selected from at least one of acetonitrile, acetone and 1, 2-dichloroethane; for example, the organic solvent is selected from acetonitrile.
In a second aspect, the present invention provides a pyridine compound containing a sulfur phenyl group, which is prepared by the method for introducing a sulfur phenyl group into the meta position of nitrogen of a pyridine ring according to any one of the previous embodiments, wherein the structural formula of the pyridine compound containing a sulfur phenyl group is as follows:
x represents halogen, R represents halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C6-C20 aryl and substituted or unsubstituted C3-C10 aromatic heterocycle, and the nucleophile is selected from secondary amines.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
This example provides a method for introducing a thiophenyl group meta to the nitrogen of a pyridine ring, the reaction scheme being as follows:
the synthesis method of the N- (2, 4-dinitrophenyl) -3-phenylpyridine salt I-a comprises the following steps: 3-phenylpyridine (5 mmol), 2, 4-dinitrobenzene halide (10 mmol), and acetone (8 mL) were added to a flask (50 mL). The resulting mixture was then stirred at 70℃for 16 hours. Then, the solvent was removed. The reaction mixture was washed with a small amount of diethyl ether and finally dried under vacuum to give I-a.
To a 25mL reaction tube was added, in air, magneton, N- (2, 4-dinitrophenyl) -3-phenylpyridine salt I-a (0.2 mmol,71.4 mg), N-phenylsulfanylphthalimide (0.2 mmol,100.2 mg), tetrahydropyrrole (0.2 mmol,14.2 mg), acetonitrile (2 mL). Then the rubber stopper is plugged, and the mixture is heated and stirred in an oil bath at 80 ℃ for 16 hours. After the completion of the reaction, the reaction system was cooled to room temperature, filtered with a glass sand funnel filled with celite, and washed with dichloromethane and ethyl acetate, the filtrates were combined, the solvent was distilled off under reduced pressure, 10mL of distilled water was added, then extracted 3 times with 30mL of ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, petroleum ether/ethyl acetate was used as a mobile phase, and 3-phenyl-5-sulfanylpyridine II-a was purified by flash silica gel column chromatography (white solid, yield 75%).
The characterization results of 3-phenyl-5-phenylsulfanylpyridine II-a are shown in FIG. 1 and FIG. 2, and are specifically analyzed as follows:
1 H NMR(400MHz,Chloroform-d)δ8.69(s,1H),8.52(s,1H),7.79(t,J＝2.1Hz,1H),7.59-7.50(m,2H),7.49-7.39(m,5H),7.38-7.29(m,3H)。
13 C NMR(101MHz,Chloroform-d)δ149.47,146.41,137.07,136.06,133.80,131.83,129.58,129.14,128.42,127.97,127.18。
HRMS(ESI)[M+H] + m/z:call for C 17 H 14 NS + :264.0841.found:264.0842。
example 2
This example provides a method for introducing a thiophenyl group meta to the nitrogen of a pyridine ring, the reaction scheme being as follows:
specifically:
the synthesis method of the N- (2, 4-dinitrophenyl) -3- (2-furyl) pyridine salt I-b is as follows: 3- (2-furyl) pyridine (5 mmol), 2, 4-dinitrobenzene halide (10 mmol) and acetone (8 mL) were added to a flask (50 mL). The resulting mixture was then stirred at 70℃for 16 hours. Then, the solvent was removed. The reaction mixture was washed with a small amount of diethyl ether and finally dried under vacuum to give I-b.
To a 25mL reaction tube was added, in air, magneton, N- (2, 4-dinitrophenyl) -3- (2-furyl) pyridinium I-b (0.2 mmol,69.4 mg), N-phenylsulfanylphthalimide (0.2 mmol,100.2 mg), tetrahydropyrrole (0.2 mmol,14.2 mg) and acetonitrile (2 mL). Then the rubber stopper is plugged, and the mixture is heated and stirred in an oil bath at 80 ℃ for 16 hours. After the completion of the reaction, the reaction system was cooled to room temperature, filtered with a glass sand funnel filled with celite, and washed with dichloromethane and ethyl acetate, the filtrates were combined, the solvent was distilled off under reduced pressure, 10mL of distilled water was added, then extracted 3 times with 30mL of ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, petroleum ether/ethyl acetate was used as a mobile phase, and 3- (2-furyl) -5-phenylsulfanylpyridine II-b (white solid, yield 60%) was purified by flash column chromatography on silica gel.
Characterization results of 3- (2-furyl) -5-phenylsulfanylpyridine II-b are shown in FIG. 3 and FIG. 4, and are specifically analyzed as follows:
1 H NMR(400MHz,Chloroform-d)δ8.60(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),7.73(t,J＝1.2Hz,1H),7.67(t,J＝2.1Hz,1H),7.50(t,J＝1.7Hz,1H),7.44-7.38(m,2H),7.38-7.28(m,3H),6.64(dd,J＝1.9,0.9Hz,1H)。
13 C NMR(101MHz,Chloroform-d)δ149.23,145.26,144.28,139.30,134.68,133.76,133.66,131.74,129.57,128.85,127.95,122.62,108.45。
HRMS(ESI)[M+H] + m/z:call for C 15 H 12 NOS + :254.0634.found:254.0635。
example 3
This example provides a method for introducing a thiophenyl group meta to the nitrogen of a pyridine ring, the reaction scheme being as follows:
in particular, the method comprises the steps of,
the synthesis method of the N- (2, 4-dinitrophenyl) -3-methylpyridine salt I-c comprises the following steps: 3-methylpyridine (5 mmol), 2, 4-dinitrobenzene halide (10 mmol) and acetone (8 mL) were added to a flask (50 mL). The resulting mixture was then stirred at 70℃for 16 hours. Then, the solvent was removed. The reaction mixture was washed with a small amount of diethyl ether and finally dried under vacuum to give I-c.
To a 25mL reaction tube was added, in air, magneton, N- (2, 4-dinitrophenyl) -3-methylpyridine salt I-c (0.2 mmol,59.0 mg), N-phenylsulfanylphthalsuccinimide (0.2 mmol,100.2 mg), tetrahydropyrrole (0.2 mmol,14.2 mg) and acetonitrile (2 mL). Then the rubber stopper is plugged, and the mixture is heated and stirred in an oil bath at 80 ℃ for 16 hours. After the completion of the reaction, the reaction system was cooled to room temperature, filtered with a glass sand funnel filled with celite, and washed with dichloromethane and ethyl acetate, the filtrates were combined, the solvent was distilled off under reduced pressure, 10mL of distilled water was added, then extracted 3 times with 30mL of ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, petroleum ether/ethyl acetate was used as a mobile phase, and 3-methyl-5-phenylsulfanylpyridine II-c (yellow liquid, yield 50%) was obtained by purification by flash silica gel column chromatography.
Characterization results of 3-methyl-5-thiophenylpyridine II-c c are shown in FIGS. 5 and 6, and are specifically analyzed as follows:
1 H NMR(400MHz,Chloroform-d)δ8.37(s,1H),8.30(s,1H),7.44(d,J＝2.1Hz,1H),7.39-7.27(m,5H),2.29(s,3H)。
13 C NMR(101MHz,Chloroform-d)δ148.44,148.26,138.72,134.22,133.81,132.84,131.51,129.47,127.71,18.29。
HRMS(ESI)[M+H] + m/z:call for C 12 H 12 NS + :202.0685.found:202.0688。
example 4
This example provides a method for introducing a thiophenyl group meta to the nitrogen of a pyridine ring, the reaction scheme being as follows:
in particular, the method comprises the steps of,
the synthesis method of the N- (2, 4-dinitrophenyl) -3-iodopyridine salt Id is as follows: 3-iodopyridine (5 mmol), 2, 4-dinitrobenzene halide (10 mmol) and acetone (8 mL) were added to a flask (50 mL). The resulting mixture was then stirred at 70℃for 16 hours. Then, the solvent was removed. The reaction mixture was washed with a small amount of diethyl ether and finally dried under vacuum to give I-d.
To a 25mL reaction tube was added, in air, magneton, N- (2, 4-dinitrophenyl) -3-iodopyridine salt I-c (0.2 mmol,81.4 mg), N-phenylsulfanylphthalimide (0.2 mmol,100.2 mg), tetrahydropyrrole (0.2 mmol,14.2 mg) and acetonitrile (2 mL). Then the rubber stopper is plugged, and the mixture is heated and stirred in an oil bath at 80 ℃ for 16 hours. After the completion of the reaction, the reaction system was cooled to room temperature, filtered with a glass sand funnel filled with celite, and washed with dichloromethane and ethyl acetate, the filtrates were combined, the solvent was distilled off under reduced pressure, 10mL of distilled water was added, then extracted 3 times with 30mL of ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, petroleum ether/ethyl acetate was used as a mobile phase, and purification was performed by flash silica gel column chromatography to give 3-iodo-5-phenylsulfanylpyridine II-d (yellow solid, yield 50%).
The characterization results of 3-iodo-5-thiophenylpyridine II-d are shown in FIG. 7, and are analyzed as follows: 1 H NMR(400MHz,Chloroform-d)δ8.57(s,1H),8.36(s,1H),7.78(t,J＝1.9Hz,1H),7.38-7.23(m,7H)。
HRMS(ESI)[M+H] + m/z:call for C 12 H 12 NS + :313.9495.found:313.9496。
comparative example 1
In particular, the method comprises the steps of,
the synthesis method of the N- (2, 4-dinitrophenyl) -pyridine salt 1e comprises the following steps: pyridine (5 mmol), 2, 4-dinitrobenzene halide (10 mmol) and acetone (8 mL) were added to a flask (50 mL). The resulting mixture was then stirred at 70℃for 16 hours. Then, the solvent was removed. The reaction mixture was washed with a small amount of diethyl ether and finally dried under vacuum to give I-c.
To a 25mL reaction tube was added, in air, magneton, N- (2, 4-dinitrophenyl) -pyridinium I-c (0.2 mmol), N-phenylsulfanylphthalimide (0.2 mmol,100.2 mg), tetrahydropyrrole (0.2 mmol,14.2 mg) and acetonitrile (2 mL). Then the rubber stopper is plugged, and the mixture is heated and stirred in an oil bath at 80 ℃ for 16 hours. After the reaction was completed, the reaction system was cooled to room temperature, filtered with a glass sand funnel filled with celite, and washed with dichloromethane and ethyl acetate, the filtrates were combined, the solvent was distilled off under reduced pressure, 10mL of distilled water was added, then extracted 3 times with 30mL of ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, petroleum ether/ethyl acetate was used as a mobile phase, and 3-phenylsulfanylpyridine II-e was hardly obtained by purification by flash column chromatography on silica gel.
In summary, the activated nitrogen-containing heterocyclic compound is used as a reaction substrate, and reacts with N-phenylthio-phthalimide under the action of a nucleophile, and phenylthio is introduced into the nitrogen-containing compound to obtain the C-3-phenylthio-substituted nitrogen-containing compound; the reaction has the advantages of good yield, high selectivity and good atom economy. The phenylthio functional group can be found in various drug molecules and pesticide compounds, and the lipophilicity and bioavailability of the bioactive molecules can be greatly enhanced after the phenylthio group is introduced into the nitrogenous heterocyclic compound. Therefore, it is of great importance to develop a method for synthesizing nitrogen-containing heterocyclic compounds containing phenylthio groups.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for introducing a thiophenyl group in the meta position of nitrogen of a pyridine ring, comprising: reacting the activated nitrogen-containing heterocyclic compound with N-phenylthio-phthalimide under the action of a nucleophilic reagent to form a target product;
wherein the activated nitrogen-containing heterocyclic compound is selected from any one of the compounds shown in the following structural formulas:
the structural formula of the N-phenylthio-phthalimide is as follows: />The structural formula of the target product is as follows: />X represents halogen, R represents halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C6-C20 aryl and substituted or unsubstituted C3-C10 aromatic heterocycle, and the nucleophile is selected from secondary amines.
2. The method for introducing a thiophenyl group into a pyridine ring at a meta position of nitrogen according to claim 1, wherein X represents chlorine or bromine.
3. The method for introducing a thiophenyl group into a meta position of a nitrogen of a pyridine ring according to claim 1, wherein R is selected from halogen, C1-C10 alkyl, C6-C15 aryl and C4-C8 aromatic heterocycle;
preferably, R is selected from halogen, C1-C5 alkyl, C6-C10 aryl, and C4-C6 oxaheterocycle;
preferably, R is selected from any one of halogen, C1-C4 alkyl, phenyl and furyl.
4. A method for introducing a thiophenyl group into the meta position of the nitrogen of a pyridine ring according to any one of claims 1 to 3, wherein the reaction conditions comprise: the molar ratio of the activated nitrogen-containing heterocyclic compound to the N-phenylthio-phthalimide is 1:1-4, wherein the dosage of the nucleophilic reagent is that the molar ratio of the activated nitrogenous heterocyclic compound is 1:1-2; the reaction temperature is 80-120 ℃ and the reaction time is 10-24 hours.
5. The method for introducing a thiophenyl group into a meta position of a nitrogen of a pyridine ring according to claim 4, wherein the reaction conditions comprise: the molar ratio of the activated nitrogen-containing heterocyclic compound to the N-phenylthio-phthalimide is 1:2, the using amount of the nucleophile is that the molar ratio of the activated nitrogen-containing heterocyclic compound is 1:1, a step of; the reaction temperature was 80℃and the time was 16 hours.
6. The method of introducing a thiophenyl group in the meta position to the nitrogen of a pyridine ring according to claim 1, wherein the step of forming the activated nitrogen-containing heterocyclic compound comprises: reacting a nitrogen-containing heterocyclic compound raw material with 2, 4-dinitrohalogen benzene; the activated nitrogen-containing heterocyclic compound formed has the following structural formula:
x represents halogen, R represents halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C6-C20 aryl, and substituted or unsubstituted C3-C10 aromatic heterocycle.
7. The method for introducing a thiophenyl group into a meta position of nitrogen of a pyridine ring according to claim 1, comprising: mixing the activated nitrogen-containing heterocyclic compound, the N-phenylthio-phthalimide and an organic solvent for reaction.
8. The method for introducing a thiophenyl group into a meta position of nitrogen of a pyridine ring according to claim 7, wherein said organic solvent is at least one selected from the group consisting of nitrile solvents, halogen alkane solvents and ketone solvents;
preferably, the organic solvent is selected from at least one of acetonitrile, acetone and 1, 2-dichloroethane;
more preferably, the organic solvent is selected from acetonitrile.
9. The method for introducing a thiophenyl group into a meta position of a nitrogen of a pyridine ring according to claim 7, wherein said nucleophile is selected from the group consisting of N-dipropylamine and tetrahydropyrrole.
10. A sulfur-containing phenyl pyridine compound prepared by introducing a sulfur phenyl group into the meta position of the nitrogen of the pyridine ring according to any one of claims 1 to 9, wherein the structure of the sulfur-containing phenyl pyridine compound is as follows:
x represents halogen, R represents halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C6-C20 aryl and substituted or unsubstituted C3-C10 aromatic heterocycle, and the nucleophile is selected from secondary amines.
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