CN104356053A - Preparation method of 2-(3-halogen phenyl) pyridine derivative - Google Patents
Preparation method of 2-(3-halogen phenyl) pyridine derivative Download PDFInfo
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- CN104356053A CN104356053A CN201410563504.4A CN201410563504A CN104356053A CN 104356053 A CN104356053 A CN 104356053A CN 201410563504 A CN201410563504 A CN 201410563504A CN 104356053 A CN104356053 A CN 104356053A
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- pyridine
- phenyl
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- iii
- phenylpyridine
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- 229910052736 halogen Inorganic materials 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 150000003222 pyridines Chemical class 0.000 title claims abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 claims abstract description 21
- -1 N-halogenated butyl diimide Chemical compound 0.000 claims abstract description 19
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 14
- 238000004440 column chromatography Methods 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 60
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
- WHXIEVDMCNQVOV-UHFFFAOYSA-N 2-(4-chlorophenyl)pyridine Chemical compound C1=CC(Cl)=CC=C1C1=CC=CC=N1 WHXIEVDMCNQVOV-UHFFFAOYSA-N 0.000 claims description 6
- WWMRJCUZPJJWBC-UHFFFAOYSA-N 4-methyl-2-phenylpyridine Chemical compound CC1=CC=NC(C=2C=CC=CC=2)=C1 WWMRJCUZPJJWBC-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- BXHXBVNRKRXSHM-UHFFFAOYSA-N (4-pyridin-2-ylphenyl)methanamine Chemical compound C1=CC(CN)=CC=C1C1=CC=CC=N1 BXHXBVNRKRXSHM-UHFFFAOYSA-N 0.000 claims description 4
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 4
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 4
- YASXBDJBCBUIHT-UHFFFAOYSA-N 2,4-diphenylpyridine Chemical compound C1=CC=CC=C1C1=CC=NC(C=2C=CC=CC=2)=C1 YASXBDJBCBUIHT-UHFFFAOYSA-N 0.000 claims description 4
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 claims description 4
- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 claims description 4
- BJATUPPYBZHEIO-UHFFFAOYSA-N 3-methyl-2-phenylpyridine Chemical compound CC1=CC=CN=C1C1=CC=CC=C1 BJATUPPYBZHEIO-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- FBQFCXDBCPREBP-UHFFFAOYSA-N 2-(4-bromophenyl)pyridine Chemical compound C1=CC(Br)=CC=C1C1=CC=CC=N1 FBQFCXDBCPREBP-UHFFFAOYSA-N 0.000 claims description 3
- KAUZPXSTHHLPFO-UHFFFAOYSA-N 2-(4-ethenylphenyl)pyridine Chemical compound C1=CC(C=C)=CC=C1C1=CC=CC=N1 KAUZPXSTHHLPFO-UHFFFAOYSA-N 0.000 claims description 3
- MHWIDTQQBWGUCD-UHFFFAOYSA-N 2-(4-fluorophenyl)pyridine Chemical compound C1=CC(F)=CC=C1C1=CC=CC=N1 MHWIDTQQBWGUCD-UHFFFAOYSA-N 0.000 claims description 3
- QQWFVLFMJHNSNI-UHFFFAOYSA-N 2-(4-iodophenyl)pyridine Chemical compound C1=CC(I)=CC=C1C1=CC=CC=N1 QQWFVLFMJHNSNI-UHFFFAOYSA-N 0.000 claims description 3
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 claims description 3
- 229940101798 4-cymene Drugs 0.000 claims description 3
- HJEZZKLAFQYBOS-UHFFFAOYSA-N 4-tert-butyl-2-phenylpyridine Chemical compound CC(C)(C)C1=CC=NC(C=2C=CC=CC=2)=C1 HJEZZKLAFQYBOS-UHFFFAOYSA-N 0.000 claims description 3
- PUKUGNXKZBWELZ-UHFFFAOYSA-N C=1C=NC(C=2C=CC=CC=2)=CC=1CC1=CC=CC=C1 Chemical compound C=1C=NC(C=2C=CC=CC=2)=CC=1CC1=CC=CC=C1 PUKUGNXKZBWELZ-UHFFFAOYSA-N 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 150000001805 chlorine compounds 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
- 229920000642 polymer Polymers 0.000 claims description 3
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 3
- VUZGGOOCZBZKGP-UHFFFAOYSA-N (2-pyridin-2-ylphenyl)methanamine Chemical compound NCC1=CC=CC=C1C1=CC=CC=N1 VUZGGOOCZBZKGP-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract 3
- 229910000071 diazene Inorganic materials 0.000 abstract 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 26
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000012230 colorless oil Substances 0.000 description 6
- TYHSWKOOZQGIFP-UHFFFAOYSA-N 2-(3-bromophenyl)-4-methylpyridine Chemical compound CC1=CC=NC(C=2C=C(Br)C=CC=2)=C1 TYHSWKOOZQGIFP-UHFFFAOYSA-N 0.000 description 4
- WLPFTJXVEBANAM-UHFFFAOYSA-N 2-(3-bromophenyl)pyridine Chemical compound BrC1=CC=CC(C=2N=CC=CC=2)=C1 WLPFTJXVEBANAM-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 230000007704 transition Effects 0.000 description 3
- GRTWYIODJKVPEV-UHFFFAOYSA-N 2-(2-methylphenyl)pyridine Chemical compound CC1=CC=CC=C1C1=CC=CC=N1 GRTWYIODJKVPEV-UHFFFAOYSA-N 0.000 description 2
- UAQDRTSYRYLQQK-UHFFFAOYSA-N 2-(3-bromophenyl)-3-methylpyridine Chemical compound CC1=CC=CN=C1C1=CC=CC(Br)=C1 UAQDRTSYRYLQQK-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GBSYGJKWBFFLSC-UHFFFAOYSA-N 2-(3-bromophenyl)-4-phenylpyridine Chemical compound BrC1=CC=CC(C=2N=CC=C(C=2)C=2C=CC=CC=2)=C1 GBSYGJKWBFFLSC-UHFFFAOYSA-N 0.000 description 1
- DDLNNTNNWVSYBY-UHFFFAOYSA-N 2-(3-bromophenyl)-4-tert-butylpyridine Chemical compound BrC=1C=C(C=CC=1)C1=NC=CC(=C1)C(C)(C)C DDLNNTNNWVSYBY-UHFFFAOYSA-N 0.000 description 1
- BMGXTZHPKNTDHN-UHFFFAOYSA-N 2-(3-chlorophenyl)pyridine Chemical compound ClC1=CC=CC(C=2N=CC=CC=2)=C1 BMGXTZHPKNTDHN-UHFFFAOYSA-N 0.000 description 1
- MADOFFWQMVKMSD-UHFFFAOYSA-N 2-(3-iodophenyl)pyridine Chemical compound IC1=CC=CC(C=2N=CC=CC=2)=C1 MADOFFWQMVKMSD-UHFFFAOYSA-N 0.000 description 1
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 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
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a preparation method of a 2-(3-halogen phenyl) pyridine derivative. The preparation method comprises the following steps: dissolving 2-phenylpyridine or substitutive 2-phenylpyridine (I) and N-halogenated butyl diimide (II) into a solvent, adding a ruthenium catalyst for reaction at the temperature of 70-150 DEG C for 24-48 hours to obtain a mixture, extracting with ethyl acetate, separating and purifying the mixture by column chromatography after the mixture is washed and dried to obtain the 2-(3-halogen phenyl) pyridine derivative (III), wherein the reaction formula of the 2-(3-halogen phenyl) pyridine derivative is shown in the specification. The preparation method has the advantages of simplicity in operation, higher yield and the like; furthermore, reaction raw materials and reaction reagents are readily available, and multiple types of product substitutes are produced.
Description
Technical field
The present invention relates to the preparation method of 2-(3-halogen phenyl) pyridine derivatives.
Background technology
Aryl halide is the important chemical intermediate of a class, and it can introduce different functional groups by transition metal-catalyzed coupling, synthesizes comparatively complex compound, as natural compounds or the medicine of some complexity.The method of the introducing halogen of classics mainly contained the nucleophilic substitution reaction of aromatic ring and the halogenating reaction of transistion metal compound intermediate in the past.They can only introduce halogen in the adjacency pair position of supplied for electronic.The phenyl ring that electron-withdrawing group replaces, due to the passivation of electron withdrawing group, the example introducing halogen in a position is considerably less.Therefore, exploitation one can high regioselectivity, and the method introducing aromatic ring halogen in a position very has meaning.
As a kind of supplementary aryl halogenation strategy, transition metal-catalyzed face position guiding and the introducing halogen of highly selective has developed into a kind of new effective ways.At present, the metal being applied to this field comprises palladium, gold, ruthenium, rhodium and copper.It is emphasized that pyridyl is proved to be more effectively to lead one of base in transition metal-catalyzed facing in a halogenating reaction.
Recently, Frost and Ackermann reports position between the catalysis of transition metal ruthenium respectively and optionally builds carbon-sulfur bond and carbon-carbon bond.But they do not realize the structure of carbon-halogen bond.
[1]A.F.Littke,G.C.Fu,Angew.Chem.2002,114,4350-4386；Angew.Chem.Int.Ed.2002,41,4176-4211；
[2]P.B.De la Mare,Electrophilic halogenation,Cambridge University Press,Cambridge,1976,chap.5.
[3]V.Snieckus,Chem.Rev.1990,90,879–933.
[4]D.Kalyani,A.R.Dick,W.Q.Anani,M.S.Sanford,Org.Lett.2006,8,2523–2526.
[5]A.R.Dick,K.L.Hull,M.S.Sanford,J.Am.Chem.Soc.2004,126,2300-2301；
[6]F.Y.Mo,J.M.Yan,D.Qiu,F.Li,Y.Zhang,J.B.Wang,Angew.Chem.Int.Ed.2010,49,2028–2032.
[7]N.
J.Wencel-Delord,F.Glorius,J.Am.Chem.Soc.2012,134,8298–8301.
[8]L.H.Wang,L.Ackermann,Chem.Commun.2014,1083-1085.
[9]L.Menini,E.V.Gusevskaya,Chem.Commun.2006,209–211
But the method being introduced aryl halogen synthesis 2-(3-halogen phenyl) pyridine derivatives by position selectivity between the catalysis of transition metal ruthenium is not also reported.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, the preparation method of a kind of 2-(3-halogen phenyl) pyridine derivatives is provided.
Technical scheme of the present invention is summarized as follows:
The preparation method of 2-(3-halogen phenyl) pyridine derivatives, comprise the steps: 2-phenylpyridine or replace 2-phenylpyridine (I), N-N-halosuccinimides (II) is dissolved in solvent, add ruthenium catalyst in 70-150 DEG C of reaction 24-48 hour, be extracted with ethyl acetate, through column chromatography separating purification after washing, drying, obtain 2-(3-halogen phenyl) pyridine derivatives (III); Its reaction formula is:
Wherein R
1for hydrogen, fluorine, chlorine, bromine, methyl, benzyl, sec.-propyl, the tertiary butyl, phenyl or methoxyl group;
R
2for hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxyl group, vinyl, oxyethyl group formyl ester group or trifluoromethyl;
X is chlorine, bromine or iodine;
Ruthenium catalyst is divalent ruthenium catalyzer or trivalent ruthenium catalyst.
Replace 2-phenylpyridine (I) and be preferably 2-(4-aminomethyl phenyl) pyridine, 2-(4-p-methoxy-phenyl) pyridine, 2-(2-p-methoxy-phenyl) pyridine, 2-(2-aminomethyl phenyl) pyridine, 2-(4-fluorophenyl) pyridine, 2-(4-chloro-phenyl-) pyridine, 2-(4-bromophenyl) pyridine, 2-(4-iodophenyl) pyridine, 2-(4-ethenylphenyl) pyridine, 2-(4-oxyethyl group formylphenyl) pyridine, 2-(4-trifluoromethyl) pyridine, 2-phenyl-4-methvl-pyridinium, 2-phenyl-4-benzyl-pyridine, 2-phenyl-4-sec.-propyl-pyridine, 2-phenyl-4-tert-Butyl-pyridin, 2-phenyl-4-methoxv-pyridine, the fluoro-pyridine of 2-phenyl-4-, the chloro-pyridine of 2-phenyl-4-, the bromo-pyridine of 2-phenyl-4-, 2-phenyl-3-methvl-pyridinium, 2-phenyl-4-phenyl-pyridin.
Ruthenium catalyst is preferably (4-cymene) ruthenous chloride dimer, (1,5-cyclooctadiene) ruthenous chloride, Ge Labu catalyzer, (1.2.3.4.5-pentamethylcyclopentadiene) ruthenous chloride polymer, ruthenium trichloride.
Solvent is estimated and is elected N,N-dimethylacetamide as, DMF, N-Methyl pyrrolidone, Isosorbide-5-Nitrae-dioxane, acetonitrile or ethylene dichloride.
The present invention has simple to operate, and reaction raw materials and reaction reagent are easy to get, and product substituting group type is various, and yield is advantages of higher comparatively.
Embodiment
The synthetic method reaction equation of 2-of the present invention (3-halogen phenyl) pyridine derivatives (III) is:
Reaction raw materials 2-phenylpyridine (I) required in each embodiment is reference literature method preparation (A.Khalafi-Nezhad, F.Panahi, Green Chem.2011,13,2408 – 2415.)
Below in conjunction with specific embodiment, the present invention is further illustrated.
Embodiment 1
The preparation of 2-(3-bromophenyl) pyridine (III-a):
By 2-phenylpyridine (I-a) (47mg, 0.3mmol), N-bromo-succinimide (II) (108mg, 0.6mmol), be dissolved in N, N-N,N-DIMETHYLACETAMIDE (0.2M, 1.5mL), add (4-cymene) ruthenous chloride dimer (9mg, 5mol%), react 24 hours at 70 DEG C, add ethyl acetate (20mL) extraction, wash with water (10mLx3), organic phase is filtered after anhydrous sodium sulfate drying, revolve and desolventize, crude product is through column chromatography separating purification, obtain 2-(3-bromophenyl) pyridine (III-a) 61mg, for colorless oil, productive rate: 87%.
1H NMR(600MHz,CDCl
3):δ8.70(t,J＝4.8,1H),8.17(t,J＝1.6,1H),7.91(d,J＝7.8,1H),7.77(td,J＝7.8,1.7,1H),7.71(d,J＝7.9,1H),7.54(dd,J＝7.9,0.9,1H),7.35(t,J＝7.9,1H),7.30–7.25(m,1H).
13C NMR(151MHz,CDCl
3)δ154.86,148.79,140.40,135.90,130.85,129.23,129.02,124.39,122.04,121.66,119.59.
Substitute the N-bromo-succinimide of the present embodiment with N-chlorosuccinimide, other same the present embodiment, experiment proves, prepares 2-(3-chloro-phenyl-) pyridine; Substitute the N-bromo-succinimide of the present embodiment with N-N-iodosuccinimide, other same the present embodiment, experiment proves, prepares 2-(3-iodophenyl) pyridine.
Embodiment 2
The preparation of (the bromo-4-p-methoxy-phenyl of 3-) pyridine (III-b):
By 2-(4-p-methoxy-phenyl) pyridine (I-b) (56mg, 0.3mmol), N-bromo-succinimide (II) (108mg, 0.6mmol), be dissolved in N, dinethylformamide (0.2M, 1.5mL), add (1, 5-cyclooctadiene) ruthenous chloride (8mg, 10mol%), react 24 hours at 150 DEG C, add ethyl acetate (20mL) extraction, wash with water (10mLx3), organic phase is filtered after anhydrous sodium sulfate drying, revolve and desolventize, crude product is through column chromatography separating purification, obtain (the bromo-4-p-methoxy-phenyl of 3-) pyridine (III-b) 72mg, for colorless oil, productive rate: 90%.
1H NMR(600MHz,CDCl
3)δ8.66(d,J＝4.6Hz,1H),8.23(d,J＝2.1Hz,1H),7.93(dd,J＝8.6,2.0Hz,1H),7.73(t,J＝7.5Hz,1H),7.65(d,J＝7.9Hz,1H),7.20(t,J＝6.0Hz,1H),6.99(d,J＝8.6Hz,1H),3.95(s,3H).
13C NMR(151MHz,CDCl
3)δ156.56,155.68,149.65,136.84,133.30,131.85,127.01,121.95,119.87,112.14,111.83,56.36.
Embodiment 3
The preparation of 2-(the bromo-4-aminomethyl phenyl of 3-) pyridine (III-c):
By 2-(4-aminomethyl phenyl) pyridine (I-c) (51mg, 0.3mmol), N-bromo-succinimide (II) (108mg, 0.6mmol), be dissolved in N-Methyl pyrrolidone (0.2M, 1.5mL), add the granny rag catalyzer (10mol%) that accords with regular rules, react 48 hours at 100 DEG C, add ethyl acetate (20mL) extraction, wash with water (10mLx3), organic phase is filtered after anhydrous sodium sulfate drying, revolve and desolventize, crude product is through column chromatography separating purification, obtain 2-(the bromo-4-aminomethyl phenyl of 3-) pyridine (III-c) 67mg, for colorless oil, productive rate: 89%.
1H NMR(600MHz,CDCl
3)δ8.61(d,J＝4.4Hz,1H),8.13(s,1H),7.75(dd,J＝7.9,1.4Hz,1H),7.67(tt,J＝9.1,4.6Hz,1H),7.62(d,J＝7.8Hz,1H),7.25(d,J＝7.9Hz,1H),7.16(t,J＝6.6Hz,1H),2.38(s,3H).
13C NMR(151MHz,CDCl
3)δ155.87,149.73,138.77,138.64,136.86,131.05,130.71,125.58,125.48,122.38,120.33,22.77.
Embodiment 4
The preparation of 2-(the bromo-4-chloro-phenyl-of 3-) pyridine (III-d)
By 2-(4-chloro-phenyl-) pyridine (I-d) (57mg, 0.3mmol), N-bromo-succinimide (II) (108mg, 0.6mmol), be dissolved in ethylene dichloride (0.2M, 1.5mL), add (1.2.3.4.5-pentamethylcyclopentadiene) ruthenous chloride polymer (5mol%), react 24 hours at 120 DEG C, add ethyl acetate (20mL) extraction, wash with water (10mLx3), organic phase is filtered after anhydrous sodium sulfate drying, revolve and desolventize, crude product is through column chromatography separating purification, obtain 2-(the bromo-4-chloro-phenyl-of 3-) pyridine (III-d) 58mg, for white solid, productive rate: 72%.
1H NMR(600MHz,CDCl
3)δ8.69(d,J＝4.6Hz,1H),8.30(d,J＝2.0Hz,1H),7.86(dt,J＝19.9,10.0Hz,1H),7.77(td,J＝7.8,1.6Hz,1H),7.69(d,J＝7.9Hz,1H),7.54(d,J＝8.4Hz,1H),7.32–7.22(m,1H).
13C NMR(151MHz,CDCl
3)δ154.81,149.87,139.35,137.02,135.09,132.08,130.52,126.66,122.99,122.87,120.40.
With 2-(4-fluorophenyl) pyridine (I-h), 2-(4-bromophenyl) pyridine (I-i), 2-(4-iodophenyl) pyridine (I-j), 2-(4-ethenylphenyl) pyridine (I-k), 2-(4-oxyethyl group formylphenyl) pyridine (I-l) or 2-(4-trifluoromethyl) pyridine (I-m) substitute 2-(4-chloro-phenyl-) pyridine (I-d) of the present embodiment respectively, other same the present embodiment, experiment proves, prepare 2-(the bromo-4-fluorophenyl of 3-) pyridine (III-h), 2-(the bromo-4-bromophenyl of 3-) pyridine (III-i), 2-(the bromo-4-iodophenyl of 3-) pyridine (III-j), 2-(the bromo-4-ethenylphenyl of 3-) pyridine (III-k), 2-(3-bromo-4-oxyethyl group formylphenyl) pyridine (III-l) or 2-(the bromo-4-trifluoromethyl of 3-) pyridine (III-m).
Embodiment 5
The preparation of 2-(the bromo-2-p-methoxy-phenyl of 3-) pyridine (III-e)
By 2-(2-p-methoxy-phenyl) pyridine (I-e) (56mg, 0.3mmol), N-bromo-succinimide (II) (108mg, 0.6mmol), be dissolved in acetonitrile (0.2M, 1.5mL), add (1, 5-cyclooctadiene) ruthenous chloride (8mg, 10mol%), react 24 hours at 80 DEG C, add ethyl acetate (20mL) extraction, wash with water (10mLx3), organic phase is filtered after anhydrous sodium sulfate drying, revolve and desolventize, crude product is through column chromatography separating purification, obtain 2-(the bromo-2-p-methoxy-phenyl of 3-) pyridine (III-e) 70mg, for colorless oil, productive rate: 88%.
1H NMR(600MHz,CDCl
3)δ8.71(d,J＝4.2Hz,1H),7.92(d,J＝2.6Hz,1H),7.80(d,J＝8.7Hz,1H),7.70(td,J＝7.8,1.7Hz,1H),7.48–7.41(m,1H),7.25–7.19(m,1H),6.87(d,J＝8.8Hz,1H),3.83(s,3H).
13C NMR(151MHz,CDCl
3)δ156.09,154.57,149.51,135.83,133.72,132.43,130.87,125.10,122.18,113.49,113.18,55.89.
Embodiment 6
The preparation of 2-(the bromo-2-aminomethyl phenyl of 3-) pyridine (III-f)
By 2-(o-tolyl) pyridine (I-f) (51mg, 0.3mmol), N-bromo-succinimide (II) (108mg, 0.6mmol), be dissolved in 1, 4-dioxane (0.2M, 1.5mL), add Grubbs catalyzer (10mol%), react 48 hours at 100 DEG C, add ethyl acetate (20mL) extraction, wash with water (10mLx3), organic phase is filtered after anhydrous sodium sulfate drying, revolve and desolventize, crude product is through column chromatography separating purification, obtain 2-(the bromo-2-aminomethyl phenyl of 3-) pyridine (III-f) 50mg, for colorless oil, productive rate: 67%.
1H NMR(600MHz,CDCl
3)δ8.70(d,J＝4.4Hz,1H),7.76(td,J＝7.7,1.6Hz,1H),7.61(d,J＝7.9Hz,1H),7.36(d,J＝7.8Hz,1H),7.33–7.26(m,2H),7.13(t,J＝7.8Hz,1H),2.37(s,3H).
13C NMR(151MHz,CDCl
3)δ159.60,149.32,142.57,136.31,135.70,132.57,128.85,126.94,126.51,124.22,122.09,20.64.
Embodiment 7
The preparation of 2-(3-bromophenyl)-4-picoline (III-g)
By 2-phenyl-4-picoline (I-g) (51mg, 0.3mmol), N-bromo-succinimide (II) (108mg, 0.6mmol), be dissolved in acetonitrile (0.2M, 1.5mL), add ruthenium trichloride (10mol%), react 24 hours at 120 DEG C, add ethyl acetate (20mL) extraction, wash with water (10mLx3), organic phase is filtered after anhydrous sodium sulfate drying, revolve and desolventize, crude product is through column chromatography separating purification, obtain 2-(3-bromophenyl)-4-picoline (III-g) 73mg, for colorless oil, productive rate: 85%.
1H NMR(400MHz,CDCl
3)δ8.47(d,J＝5.0Hz,1H),8.07(t,J＝1.7Hz,1H),7.82(d,J＝7.8Hz,1H),7.49–7.41(m,2H),7.25(t,J＝7.9Hz,1H),7.01(d,J＝7.5Hz,1H),2.34(s,3H).
13C NMR(151MHz,CDCl
3)δ154.73,148.50,146.98,140.53,130.69,129.16,129.00,124.41,122.66,121.95,120.56,20.20.
With 2-phenyl-4-benzyl-pyridine (I-n), 2-phenyl-4-sec.-propyl-pyridine (I-o), 2-phenyl-4-tert-Butyl-pyridin (I-p), 2-phenyl-4-methoxv-pyridine (I-q), the fluoro-pyridine of 2-phenyl-4-(I-r), the chloro-pyridine of 2-phenyl-4-(I-s), the bromo-pyridine of 2-phenyl-4-(I-t), 2-phenyl-3-methvl-pyridinium (I-u) or 2-phenyl-4-phenyl-pyridin (I-v) substitutes 2-phenyl-4-methvl-pyridinium (I-g) of the present embodiment respectively, other same the present embodiment, experiment proves, prepare 2-(3-bromophenyl)-4-benzyl-pyridine (III-n), 2-(3-bromophenyl)-4-sec.-propyl-pyridine (III-o), 2-(3-bromophenyl)-4-tert-Butyl-pyridin (III-p), 2-(3-bromophenyl)-4-methoxv-pyridine (III-q), the 2-fluoro-pyridine of (3-bromophenyl)-4-(III-r), the 2-chloro-pyridine of (3-bromophenyl)-4-(III-s), the 2-bromo-pyridine of (3-bromophenyl)-4-(III-t), 2-(3-bromophenyl)-3-methvl-pyridinium (III-u) or 2-(3-bromophenyl)-4-phenyl-pyridin (III-v).
The above; be only section Example of the present invention, not any pro forma restriction done to the present invention, every any simple amendment above-described embodiment done according to technical spirit of the present invention; equivalent variations and modification, all belong to protection scope of the present invention.
Claims (4)
- The preparation method of 1.2-(3-halogen phenyl) pyridine derivatives, it is characterized in that comprising the steps: 2-phenylpyridine or replacing 2-phenylpyridine (I), N-N-halosuccinimides (II) is dissolved in solvent, add ruthenium catalyst in 70-150 DEG C of reaction 24-48 hour, be extracted with ethyl acetate, through column chromatography separating purification after washing, drying, obtain 2-(3-halogen phenyl) pyridine derivatives (III); Its reaction formula is:Wherein R 1for hydrogen, fluorine, chlorine, bromine, methyl, benzyl, sec.-propyl, the tertiary butyl, phenyl or methoxyl group;R 2for hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxyl group, vinyl, oxyethyl group formyl ester group or trifluoromethyl;X is chlorine, bromine or iodine;Ruthenium catalyst is divalent ruthenium catalyzer or trivalent ruthenium catalyst.
- 2. preparation method according to claim 1, it is characterized in that described replacement 2-phenylpyridine (I) is for 2-(4-aminomethyl phenyl) pyridine, 2-(4-p-methoxy-phenyl) pyridine, 2-(2-p-methoxy-phenyl) pyridine, 2-(2-aminomethyl phenyl) pyridine, 2-(4-fluorophenyl) pyridine, 2-(4-chloro-phenyl-) pyridine, 2-(4-bromophenyl) pyridine, 2-(4-iodophenyl) pyridine, 2-(4-ethenylphenyl) pyridine, 2-(4-oxyethyl group formylphenyl) pyridine, 2-(4-trifluoromethyl) pyridine, 2-phenyl-4-methvl-pyridinium, 2-phenyl-4-benzyl-pyridine, 2-phenyl-4-sec.-propyl-pyridine, 2-phenyl-4-tert-Butyl-pyridin, 2-phenyl-4-methoxv-pyridine, the fluoro-pyridine of 2-phenyl-4-, the chloro-pyridine of 2-phenyl-4-, the bromo-pyridine of 2-phenyl-4-, 2-phenyl-3-methvl-pyridinium, 2-phenyl-4-phenyl-pyridin.
- 3. method according to claim 1, it is characterized in that described ruthenium catalyst is (4-cymene) ruthenous chloride dimer, (1,5-cyclooctadiene) ruthenous chloride, lattice granny rag catalyzer, (1.2.3.4.5-pentamethylcyclopentadiene) ruthenous chloride polymer, ruthenium trichloride.
- 4. preparation method according to claim 1, is characterized in that described solvent is N,N-dimethylacetamide, DMF, N-Methyl pyrrolidone, Isosorbide-5-Nitrae-dioxane, acetonitrile or ethylene dichloride.
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Cited By (2)
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| CN104926714A (en) * | 2015-07-02 | 2015-09-23 | 天津大学 | Preparation method of 2-chlorine-N-(4-chlorine-3-(2-pyridyl)phenyl)-4-methyl sulfone phenyl benzamide |
| CN111499569A (en) * | 2020-04-24 | 2020-08-07 | 华中科技大学 | Method for simultaneously synthesizing 5-bromo-2-phenylpyridine and 2- (4-bromophenyl) pyridine in one step without metal catalysis |
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