CN107459533B - Benzimidazole-indole skeleton phosphine ligand and preparation method and application thereof - Google Patents
Benzimidazole-indole skeleton phosphine ligand and preparation method and application thereof Download PDFInfo
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- CN107459533B CN107459533B CN201610389908.5A CN201610389908A CN107459533B CN 107459533 B CN107459533 B CN 107459533B CN 201610389908 A CN201610389908 A CN 201610389908A CN 107459533 B CN107459533 B CN 107459533B
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- Prior art keywords
- alkyl
- indol
- benzimidazole
- reaction
- added
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 106
- 239000003446 ligand Substances 0.000 title claims abstract description 85
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title abstract description 18
- UGPUQHVITYCTEV-UHFFFAOYSA-N 1h-benzimidazole;1h-indole Chemical group C1=CC=C2NC=CC2=C1.C1=CC=C2NC=NC2=C1 UGPUQHVITYCTEV-UHFFFAOYSA-N 0.000 title description 3
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical class [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims description 101
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 78
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 66
- -1 alkyl tosylate Chemical compound 0.000 claims description 49
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 42
- 239000000543 intermediate Substances 0.000 claims description 39
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 39
- 229910052763 palladium Inorganic materials 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 26
- 229910052723 transition metal Inorganic materials 0.000 claims description 25
- 150000003624 transition metals Chemical class 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 23
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 22
- 239000003054 catalyst Substances 0.000 claims description 19
- 238000006880 cross-coupling reaction Methods 0.000 claims description 19
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims description 18
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 238000005859 coupling reaction Methods 0.000 claims description 12
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 11
- 150000001347 alkyl bromides Chemical class 0.000 claims description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000012312 sodium hydride Substances 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims description 7
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 7
- 150000001500 aryl chlorides Chemical class 0.000 claims description 6
- USJRLGNYCQWLPF-UHFFFAOYSA-N chlorophosphane Chemical class ClP USJRLGNYCQWLPF-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- 241000274177 Juniperus sabina Species 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 2
- 238000007333 cyanation reaction Methods 0.000 claims description 2
- 239000012038 nucleophile Substances 0.000 claims description 2
- 238000006254 arylation reaction Methods 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 abstract description 7
- 125000005429 oxyalkyl group Chemical group 0.000 abstract description 7
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract description 5
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 abstract description 5
- 125000001309 chloro group Chemical group Cl* 0.000 abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 3
- 125000004076 pyridyl group Chemical group 0.000 abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 65
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 34
- 229910052757 nitrogen Inorganic materials 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- 230000003197 catalytic effect Effects 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 17
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
- UVNXNSUKKOLFBM-UHFFFAOYSA-N imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=CSC2=NC=CN21 UVNXNSUKKOLFBM-UHFFFAOYSA-N 0.000 description 14
- 238000000605 extraction Methods 0.000 description 13
- 239000005457 ice water Substances 0.000 description 13
- 229910052751 metal Inorganic materials 0.000 description 11
- 239000002184 metal Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 7
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 239000004809 Teflon Substances 0.000 description 4
- 229920006362 Teflon® Polymers 0.000 description 4
- 150000001543 aryl boronic acids Chemical class 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- ZBCKWHYWPLHBOK-UHFFFAOYSA-N cyclohexylphosphane Chemical compound PC1CCCCC1 ZBCKWHYWPLHBOK-UHFFFAOYSA-N 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 238000004817 gas chromatography Methods 0.000 description 4
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical group N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- RMNIZOOYFMNEJJ-UHFFFAOYSA-K tripotassium;phosphate;hydrate Chemical compound O.[K+].[K+].[K+].[O-]P([O-])([O-])=O RMNIZOOYFMNEJJ-UHFFFAOYSA-K 0.000 description 3
- NPDACUSDTOMAMK-UHFFFAOYSA-N 4-Chlorotoluene Chemical compound CC1=CC=C(Cl)C=C1 NPDACUSDTOMAMK-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical group 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- REJGOFYVRVIODZ-UHFFFAOYSA-N phosphanium;chloride Chemical class P.Cl REJGOFYVRVIODZ-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- AAAXMNYUNVCMCJ-UHFFFAOYSA-N 1,3-diiodopropane Chemical compound ICCCI AAAXMNYUNVCMCJ-UHFFFAOYSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 238000006411 Negishi coupling reaction Methods 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- GGVGWZSSCHSRMG-UHFFFAOYSA-N chloro(cyclohexyl)phosphane Chemical compound ClPC1CCCCC1 GGVGWZSSCHSRMG-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001041 indolyl group Chemical group 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
- 238000002955 isolation Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 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
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- KPZYAGQLBFUTMA-UHFFFAOYSA-K tripotassium;phosphate;trihydrate Chemical compound O.O.O.[K+].[K+].[K+].[O-]P([O-])([O-])=O KPZYAGQLBFUTMA-UHFFFAOYSA-K 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- 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
- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
The invention provides a phosphine ligand of a 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole skeleton, and a preparation method and application thereof. The 2- (3- (two)Phosphine ligands substituted with phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole backbones, the structures of which are shown below:wherein, R is1、R2Independently one of hydrogen radical, C1-10 alkyl, alkoxy, oxyalkyl, phenyl and pyridyl, and R is3Is phenyl or alkyl, said R4、R5Independently is one of hydrogen group, alkyl group, alkoxy group, oxyalkyl group, phenyl group, fluoro group and chloro group.
Description
Technical Field
The invention belongs to the technical field of organic compounds and synthesis, relates to a phosphine ligand with a benzimidazole-indole skeleton, and a preparation method and application thereof, and particularly relates to a phosphine ligand with a 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole skeleton, and a preparation method and application thereof.
Background
Transition metal catalyzed cross-coupling reactions are one of the important methods of forming carbon-carbon bonds, and have been extensively studied and have made tremendous progress in the last forty years since the 70's of the last century. In 2010, nobel prize was awarded to richarded, a pioneer scientist of three-position palladium-catalyzed coupling reactions, Heck (Heck reaction), nelumbo-honor one (negishi reaction), and Suzuki reaction, to show their outstanding performance in palladium-catalyzed coupling reactions.
In metal-catalyzed coupling reactions, ligands play a very important role, playing a significant role in many areas, such as yield, cost, reaction by-products, atom economy, functional group compatibility, and the like. The ligand can effectively adjust the performance of the catalyst, and the coupling reaction is performed more perfectly. At present, the commonly used ligands are organic phosphine compounds generally, and the researches on phosphine ligands for years show that the slight changes of the position, size, steric hindrance, electrical property and the like of a substituent group on a ligand framework can generate important influence on the reaction result. The phosphine ligand of the indole skeleton is a novel ligand in metal organic chemistry, and has the advantages that the ligand is insensitive to air, and the space structure and the electric property of the ligand can be adjusted by changing a substituent group on indole; in addition, the coordination performance of the ligand can be changed by changing the substituent group on the phosphorus atom.
Since the beginning of the last century, phosphine ligands have begun to be used in transition metal catalyzed organic synthesis reactions and have gradually attracted a great deal of attention. In addition, Suzuki cross-coupling is still a very challenging area to date. The key to solving the problem of coupling and bonding is to find a suitable catalytic system, especially to find an effective ligand. Furthermore, in the development of ligands, researchers have also attempted to design more active ligands for use in coupling reactions with different types of electrophiles, where low amounts of metal-catalyzed coupling reactions have remained a scientific challenge to date. Therefore, the design and synthesis of the phosphine ligand which is easy to prepare, stable in structure and high in catalytic activity and the application of the phosphine ligand in the low-dosage metal catalytic coupling reaction have far-reaching significance.
Disclosure of Invention
The invention aims to provide a phosphine ligand of a 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton, and aims to solve the problems that the existing phosphine ligand cannot meet the requirements of easiness in preparation, stable structure, high catalytic activity and low dosage of a transition metal catalyst in cross-coupling reaction.
Another object of the present invention is to provide a method for preparing a phosphine ligand having a 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton.
Still another object of the present invention is to provide a use of a phosphine ligand of 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton.
The invention is realized by the following formula, wherein the structure of the phosphine ligand of the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole skeleton is shown as the following formula:
wherein, R is1、R2Independently one of hydrogen radical, C1-10 alkyl, alkoxy, oxyalkyl, phenyl and pyridyl, and R is3Is phenyl or alkyl, said R4、R5Independently is one of hydrogen group, alkyl group, alkoxy group, oxyalkyl group, phenyl group, fluoro group and chloro group.
And, a method for preparing a phosphine ligand of 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton, comprising the steps of:
dissolving indole-2-carboxylic acid, o-phenylenediamine and sulfuric acid in ethylene glycol, and stirring for 2-36 hours under the condition of heating reflux to obtain a (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate;
dissolving the (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate, sodium hydride or potassium hydroxide in tetrahydrofuran or dimethylformamide, and stirring at 0 ℃ or room temperature for 0.5-2 hours; then adding dimethyl sulfate or alkyl bromide or toluene sulfonic acid alkyl ester, stirring for 2-36 hours at room temperature to obtain 2- (N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole;
dissolving the 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole in tetrahydrofuran, adding N-bromosuccinimide at the temperature of 0 ℃ to form a mixture, and stirring the mixture at the temperature of 15-50 ℃ to react for 30 minutes to 4 hours to obtain a 2- (N-alkyl-3-bromo-indol-2-yl) -N-alkyl-benzimidazole intermediate;
dissolving the 2- (N-alkyl-3-bromo-indol-2-yl) -N-alkyl-benzimidazole intermediate in tetrahydrofuran, adding N-butyllithium, reacting at-75 to-80 ℃ for 0.5 to 2 hours, adding disubstituted chlorophosphine, and reacting at room temperature for 12 to 48 hours to obtain the 2- (3- (disubstituted phosphino) -N-alkylindol-2-yl) -N-alkyl-benzimidazolephosphine ligand.
And the application of the phosphine ligand of 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole skeleton as the synergist of transition metal catalyst in cross-coupling reaction.
The phosphine ligand of the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole framework can form a complex with a stable structure with transition metal such as palladium metal, so that the catalytic activity of the catalytic reaction of the transition metal such as palladium is improved, and the phosphine ligand has the advantages of wide application range, good selectivity and mild reaction conditions. The catalytic system formed by the phosphine ligand of the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole skeleton and transition metal such as palladium metal can be widely applied to cross coupling Reaction catalyzed by the transition metal such as Suzuki Reaction (Suzuki Reaction) to prepare various synthetic products such as biaryl compounds, and has great application potential in the synthesis of natural products and drug intermediates. The catalytic amount of palladium metal in the catalytic system can be as low as 0.0025 mol%, the separation yield can be as high as 99%, and the catalyst is compatible with functional groups such as ester, aldehyde, cyanogen, methoxyl and the like. In addition, the phosphine ligand with the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton has stability to air and moisture and is easy to store; and the space structure and the electric property of the ligand can be adjusted by changing the substituent group on the indole, so that the coordination performance of the ligand is changed.
The preparation method of the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole skeleton phosphine ligand provided by the invention has the advantages of simple and easily obtained raw materials, simple method and high total yield.
The phosphine ligand of the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole framework provided by the invention can be widely used as a synergist of a transition metal catalyst, and can be used for a cross-coupling reaction to form a complex with a stable structure with a transition metal such as palladium metal, so that the catalytic activity of the transition metal such as palladium during a catalytic reaction is improved, the catalytic activity of the transition metal catalyst such as palladium catalyst can be as low as 0.0025 mol%, and the separation yield is as high as 99%.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention provides a phosphine ligand of a 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole skeleton, and the structure of the phosphine ligand is shown as the following formula:
wherein, R is1、R2Independently one of hydrogen radical, C1-10 alkyl, alkoxy, oxyalkyl, phenyl and pyridyl, and R is3Is phenyl or alkyl, said R4、R5Independently is one of hydrogen group, alkyl group, alkoxy group, oxyalkyl group, phenyl group, fluoro group and chloro group.
In the above structural formula, it is particularly preferable that R is4Or R5Wherein said alkyl group includes C1-10 alkyl group, and said R1Or R2Or R4 or R5The C1-10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-10 alkyl; the alkoxy group comprises methoxy and ethoxy; the oxyalkyl group includes an oxymethyl group. The R is3The alkyl group includes isopropyl, cyclohexyl, ethyl, tert-butyl, and methylethyl.
Further, as a preferred embodiment, the R group4Is one of hydrogen radical, alkyl, chlorine radical, oxymethyl, trifluoromethyl and naphthyl; as another preferred embodiment, said R5Is one of hydrogen radical, alkyl, oxymethyl, fluorine, trifluoromethyl and naphthyl.
The phosphine ligand of the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole skeleton in the preferable condition can be combined with transition metal such as palladium metal to obtain a catalytic system with better catalytic effect, and various synthetic products such as biaryl compounds are prepared.
The phosphine ligand of the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton provided by the embodiment of the invention can form a complex with a stable structure with transition metal such as palladium metal, so that the catalytic activity of the catalytic reaction of the transition metal such as palladium is improved, and the phosphine ligand has the advantages of wide application range, good selectivity and mild reaction conditions. The catalytic system formed by the phosphine ligand of the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole skeleton and transition metal such as palladium metal can be widely applied to cross coupling reaction catalyzed by the transition metal such as Suzuki coupling reaction (Suzuki reaction) to prepare various synthetic products such as biaryl compounds, and has great application potential in the synthesis of natural products and drug intermediates. The catalytic amount of palladium metal in the catalytic system can be as low as 0.0025 mol%, the separation yield can be as high as 99%, and the catalyst is compatible with functional groups such as ester, aldehyde, cyanogen, methoxyl and the like. In addition, the phosphine ligand with the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton disclosed in the embodiment of the invention has stability to air and moisture and is easy to store; and the space structure and the electric property of the ligand can be adjusted by changing the substituent groups on the indole or the benzimidazole, so that the coordination performance of the ligand is changed.
The phosphine ligands of the- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton described in the examples of the present invention can be prepared by the following methods.
The embodiment of the invention also provides a preparation method of the phosphine ligand of the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton, which comprises the following steps:
s01, dissolving indole-2-carboxylic acid, o-phenylenediamine and sulfuric acid in ethylene glycol, and stirring for 2-36 hours under the condition of heating reflux to obtain a (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate;
s02, dissolving the (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate, sodium hydride or potassium hydroxide in tetrahydrofuran or dimethylformamide, stirring at 0 ℃ or room temperature for 0.5-2 hours, adding dimethyl sulfate or alkyl bromide or alkyl tosylate, and stirring at room temperature for 2-36 hours to obtain 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole;
s03, dissolving the 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole in tetrahydrofuran, adding N-bromosuccinimide at the temperature of 0 ℃ to form a mixture, and stirring the mixture at the temperature of 15-50 ℃ to react for 30 minutes to 4 hours to obtain a 2- (N-alkyl-3-bromo-indol-2-yl) -N-alkyl-benzimidazole intermediate;
s04, dissolving the 2- (N-alkyl-3-bromo-indol-2-yl) -N-alkyl-benzimidazole intermediate in tetrahydrofuran, adding N-butyl lithium, reacting at-75 to-80 ℃ for 0.5 to 2 hours, adding disubstituted chlorophosphine, and reacting at room temperature for 12 to 48 hours to obtain the 2- (3- (disubstituted phosphino) -N-alkyl indol-2-yl) -N-alkyl-benzimidazole phosphine ligand.
Specifically, in step S01, as a preferred example, in order to obtain the (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate with high purity and high yield, the molar ratio of the indole-2-carboxylic acid, the o-phenylenediamine, and the sulfuric acid is 1.05 to 3.0:1.0:1.05 to 3.0. Particularly preferably, the indole-2-carboxylic acid and the o-phenylenediamine are fed according to the molar ratio of 1.05-3.0:1.0, then ethylene glycol is added as a reactant and a solvent, and the mixture is slowly heated until the reactant is completely dissolved; then slowly adding sulfuric acid with the ratio of 1.0:1.05-3.0 at room temperature, heating and refluxing for reaction for 2-36 hours, specifically, the reaction time can be 5 hours, 10 hours, 24 hours and the like. The reaction formula of step S01 is as follows, and the reaction time can be adjusted with reference to the above range.
Preferably, after the reaction is finished, pouring the reactant into ice water to stop the reaction, adding ammonium hydroxide to neutralize until the pH value is 7, adding diethyl ether to extract and separate; the organic phase is concentrated and purified by column chromatography to give a brown solid (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate.
In the above step S02, as a preferred example, in order to obtain the 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole intermediate with high purity and yield, the molar ratio of the (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate, alkyl bromide and potassium hydroxide or sodium hydride is 1.0:3.0-8.0:3.0-10.0, wherein the alkyl bromide may be replaced by alkyl tosylate or dimethyl sulfate. As a particularly preferred example, potassium hydroxide or sodium hydride, dimethylformamide, alkyl bromide or alkyl tosylate is used as the reaction system for preparing the 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole intermediate; as another particularly preferred example, sodium hydride, tetrahydrofuran, dimethyl sulfate are employed as the reaction system for preparing the 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole intermediate. Specifically, the mixture of the (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate, the alkyl bromide and the potassium hydroxide in the molar ratio of 1.0:3.0-8.0:3.0-10.0 is stirred completely and uniformly in dimethylformamide at room temperature for 2-36 hours, and water is added to stop the reaction after the intermediate is completely consumed by thin layer chromatography detection. The reaction formula of the above step S02 is as follows:
further preferably, dichloromethane is added to the reaction and the organic layer is separated by extraction, dried over magnesium sulfate and the organic phase is concentrated and purified by column chromatography to give the 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole intermediate.
In the above step S03, as a preferred example, in order to obtain the 2- (N-alkyl-3-bromo-indol-2-yl) -N-alkyl-benzimidazole intermediate with high purity and high yield, the molar ratio of the 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole to the N-bromosuccinimide is 1.0: 1.05-3.0. Specifically, the 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole is dissolved in tetrahydrofuran, N-bromosuccinimide dissolved in tetrahydrofuran is added at a temperature of 0 ℃ in a molar ratio of 1:1.05-3.0, and the mixture is stirred completely at room temperature or at 25-50 ℃ for 30 minutes to 4 hours or until the reaction is completed. The reaction formula of the above step S03 is as follows:
preferably, after detecting that the 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole intermediate is completely consumed by thin layer chromatography, pouring the mixture into ice water to stop reaction, adding dichloromethane for extraction, and separating; the organic phase is concentrated after drying over magnesium sulphate and purified by column chromatography to give the 2- (N-alkyl-3-bromo-indol-2-yl) -N-alkyl-benzimidazole intermediate.
In the above step S04, as a preferred example, in order to obtain the 2- (3- (disubstituted phosphino) -N-alkylindol-2-yl) -N-alkyl-benzimidazolephosphine ligand with high purity and yield, the molar ratio of the 2- (N-alkyl-3-bromo-indolin-2-yl) -N-alkyl-benzimidazolium intermediate, N-butyllithium and disubstituted chlorophosphine is 1:1.1-3.0: 1.1-2.0. In order to obtain preferable reaction results, the reaction is carried out at-75 to-80 ℃ for 0.5 to 2 hours, and particularly at-78 ℃ for 1 hour. Further preferably, the 2- (N-alkyl-3-bromo-indol-2-yl) -N-alkyl-benzimidazole is dissolved in tetrahydrofuran, N-butyllithium is added at a ratio of 1.0:1.1-3.0 at-78 ℃, and the mixture is stirred uniformly for 0.5-2 hours; then, disubstituted phosphine chloride is added in the ratio of 1.0:1.1-2.0, and the reaction is stirred at room temperature for 12-48 hours. The reaction formula of step S04 is as follows, and the reaction temperature and time can be adjusted by referring to the above ranges.
Further preferably, the reduced pressure to remove all solvent in the reactants; washing twice with cold ethanol/methanol mixed solvent to obtain powdered 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole phosphine ligand.
The preparation method of the phosphine ligand with the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton provided by the embodiment of the invention has the advantages of simple and easily obtained raw materials, simple method and high total yield.
The embodiment of the invention also provides application of a phosphine ligand of a 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton as a synergist of a transition metal catalyst in cross coupling reaction.
Wherein the cross-coupling reaction includes, but is not limited to, reaction of aryl chloride and organic titanium nucleophile, suzuki coupling reaction, sabina coupling reaction, polyarenation of polyfluorophenyl group, boron-based coupling reaction, cyanation reaction, and α -monoarylation of carbonyl compound.
Preferably, the transition metal catalyst is a palladium catalyst.
The phosphine ligand of the 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton provided by the embodiment of the invention can be widely used as a synergist of a transition metal catalyst, and can be used for a cross-coupling reaction to form a complex with a stable structure with a transition metal such as palladium metal, so that the catalytic activity of the transition metal such as palladium during a catalytic reaction is improved, the catalytic activity of the transition metal catalyst such as palladium catalyst can be as low as 0.0025 mol%, and the separation yield is as high as 99%.
In the embodiment of the invention, the room temperature refers to the room temperature of 10-30 ℃.
The following description is made with reference to specific embodiments.
Example one
An indomidazolylphosphine ligand, the structure of which is 2- (3- (diphenylphosphino) -1-methyl-1H-indol-2-yl) -N-methyl-benzimidazole shown as the following formula,
the preparation method of the 2- (3- (diphenylphosphino) -1-methyl-1H-indole-2-yl) -N-methyl-benzimidazole comprises the following steps:
in a 500 ml round bottom flask, 8.30 g indole-2-carboxylic acid (52mmol) was added, then 5.40 g o-phenylenediamine (50mmol) was added, 50ml ethylene glycol was slowly added, heating was slowly continued until the reaction mass was completely dissolved, then 2.8 ml sulfuric acid (53mmol) was slowly added at room temperature, and heating was refluxed for 2-36 hours. The reaction was terminated by pouring the mixture into ice water, and then 100 ml of ammonium hydroxide was added to the system to neutralize the pH, and 150 ml of ether was added three times each for extraction and separation. The organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase is concentrated and purified by column chromatography to obtain a brown solid (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate 10.0 g, with a yield of 89%, which can be directly put into the next reaction.
In a 100 ml three-necked flask evacuated with nitrogen, 2.1 g of sodium hydride (33mmol) was weighed in under nitrogen, 10ml of freshly distilled tetrahydrofuran was added and stirred uniformly. Then 3.5 g of (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate (15mmol) dissolved in 25 ml of freshly distilled tetrahydrofuran solution were slowly added and the reaction was allowed to proceed at room temperature for 1 hour. Then, 3.2 ml of dimethyl sulfate (33mmol) was added thereto, and the reaction was carried out at room temperature for 1 hour. When the reaction was completed, 5ml of ethanol was added to the system, and then all the solution was taken out under reduced pressure. 50ml of ethyl acetate and 50ml of water were added to the system. 50ml of ethyl acetate are added for extraction three times, and the organic phases are combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to give 3.09 g of the intermediate 1-methyl-2- (1-methyl-1H-indol-2-yl) -1H-benzo [ d ] imidazole, in 82% yield, which was directly used in the next step.
In a 100 ml round bottom flask, 1.31 g of 1-methyl-2- (1-methyl-1H-indol-2-yl) -1H-benzo [ d ] imidazole (5mmol) was weighed in, 20ml of tetrahydrofuran was added and stirred well. 0.99 g of N-bromosuccinimide (5.6mmol) dissolved in 10ml of tetrahydrofuran is then added slowly in an ice-water bath at 0 ℃ and the mixture is stirred completely at room temperature or at 25 ℃ to 50 ℃ for more than 30 minutes until the reaction is complete. After the reaction of the starting materials was completed, the reaction was stopped by pouring the mixture into 20ml of ice water, 20ml of dichloromethane was added, extraction was carried out three times by adding 20ml of water and dichloromethane, the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to give 1.38 g of 1-methyl-2- (3-bromo-1-methyl-1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate in 82% yield, which was directly fed to the next reaction.
In a 100 ml three-necked flask purged with nitrogen, 1.36 g of 1-methyl-2- (3-bromo-1-methyl-1H-indol-2-yl) -1H-benzo [ d ] are weighed]Imidazole (4mmol) is added with 10ml of new evaporated tetrahydrofuran under the condition of introducing nitrogen and stirred evenly. The mixture was cooled to-78 ℃ with ice, and n-butyllithium (9.2mmol) was added thereto to conduct a reaction for 0.5 to 2 hours. Then, 1.49 ml of diphenyl phosphine chloride (8.3mmol) and 20ml of freshly distilled tetrahydrofuran were mixed and addedAnd (4) pyran. Slowly raising the temperature to room temperature for reaction for 12-48 hours. All solutions were removed under reduced pressure and washed twice with cold ethanol/methanol mixtures or purified by column chromatography to give the pure product 2- (3- (diphenylphosphino) -1-methyl-1H-indol-2-yl) -N-methyl-benzimidazole in 1.34 g as a pink powder with a yield of 52%.1H NMR(400MHz,CDCl3)δ3.59(s,3H),3.76(s,3H),5.31(1H),7.01(t,J=7.6Hz,1H),7.14(s,3H),7.18-7.39(m,11H),7.46(d,J=8.4Hz,1H),7.54-7.58(m,2H),7.89-7.91(m,1H)。
Example two
An indomidazolylphosphine ligand, the structure of which is 2- (3- (diphenylphosphino) -1-ethyl-1H-indol-2-yl) -N-ethyl-benzimidazole shown as the following formula,
the preparation method of the 2- (3- (diphenylphosphino) -1-ethyl-1H-indol-2-yl) -N-ethyl-benzimidazole comprises the following steps:
in a 100 ml three-necked flask purged with nitrogen, 3.96 g of (1H-indol-2-yl) -1H-benzo [ d ] imidazole (17mmol) was weighed, 70 ml of dimethylformamide was added, and the mixture was stirred uniformly. Then 5.63 g potassium hydroxide (100mmol) was added and the reaction was stirred thoroughly at room temperature for 2-36 hours, and as most of the potassium hydroxide dissolved, a thick cloudy solution was formed, 5.0 ml ethyl bromide (67mmol) was added and the reaction was allowed to proceed at room temperature for 18-24 hours. After the reaction of the starting materials was completed, the reaction was stopped by spotting, 70 ml of water and 40 ml of dichloromethane were added to the system, and then 40 ml of dichloromethane was added three times to extract, and the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to give 2.60 g of the intermediate 1-ethyl-2- (1-ethyl-1H-indol-2-yl) -1H-benzo [ d ] imidazole, in 53% yield, which was directly used in the next reaction.
In a 100 ml round bottom flask, 1.44 g of 1-ethyl-2- (1-ethyl-1H-indol-2-yl) -1H-benzo [ d ] imidazole (5mmol) was weighed in, 20ml of tetrahydrofuran was added and stirred well. 0.99 g of N-bromosuccinimide (5.6mmol) dissolved in 10ml of tetrahydrofuran is then added slowly in an ice-water bath at 0 ℃ and the mixture is stirred completely at room temperature or at 25 ℃ to 50 ℃ for more than 30 minutes until the reaction is complete. After the reaction of the starting materials was completed, the reaction was stopped by pouring the mixture into 20ml of ice water, 20ml of dichloromethane was added, extraction was carried out three times by adding 20ml of water and dichloromethane, the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to give 1.56 g of 1-ethyl-2- (3-bromo-1-ethyl-1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate in 85% yield, which was directly fed to the next reaction.
In a 100 ml three-necked flask evacuated with nitrogen, 1.46 g of 1-ethyl-2- (3-bromo-1-ethyl-1H-indol-2-yl) -1H-benzo [ d ] are weighed]Imidazole (4mmol) is added with 10ml of new evaporated tetrahydrofuran under the condition of introducing nitrogen and stirred evenly. The mixture was cooled to-78 ℃ with ice, and n-butyllithium (9.2mmol) was added thereto to conduct a reaction for 0.5 to 2 hours. 1.49 ml of diphenyl phosphonium chloride (8.3mmol) and 20ml of freshly distilled tetrahydrofuran, which had been mixed, were further added. Slowly raising the temperature to room temperature for reaction for 12-48 hours. All solutions were removed under reduced pressure and washed twice with cold ethanol/methanol mixtures or purified by column chromatography to give the pure product 2- (3- (diphenylphosphino) -1-ethyl-1H-indol-2-yl) -N-ethyl-benzimidazole in 1.34 g as a white powder with a yield of 71%.1H NMR(400MHz,CDCl3)δ1.18(t,J=7.2Hz,3H),1.33(t,J=7.2Hz,3H),3.91-4.01(m,2H),4.08-4.17(m,1H),4.28-4.37(m,1H),6.96(t,J=7.6Hz,1H),7.12-7.14(m,4H),7.26-7.50(m,12H),7.87-7.89(m,1H)。
EXAMPLE III
An indomidazolylphosphine ligand, the structure of which is 2- (3- (diphenylphosphino) -1-N-propyl-1H-indol-2-yl) -N-N-propyl-benzimidazole,
the preparation method of the 2- (3- (diphenylphosphino) -1-N-propyl-1H-indole-2-yl) -N-N-propyl-benzimidazole comprises the following steps:
in a 100 ml three-necked flask purged with nitrogen, 1.86 g of (1H-indol-2-yl) -1H-benzo [ d ] imidazole (8mmol) was weighed, and 30 ml of dimethylformamide was added and stirred uniformly. Then 3.58 g of potassium hydroxide (64mmol) was added and the reaction was stirred thoroughly at room temperature for 2-36 hours, and as most of the potassium hydroxide dissolved, a thick cloudy solution was formed, 3.12 ml of 1-iodopropane (32mmol) was added and the reaction was allowed to proceed at room temperature for 18-24 hours. After the reaction of the starting materials was completed, the reaction was stopped by spotting, 30 ml of water and 20ml of dichloromethane were added to the system, extraction was carried out by adding 20ml of dichloromethane three times, the organic phases were combined, and dried over anhydrous magnesium sulfate. The organic phase is concentrated and purified by column chromatography to obtain 1.88 g of 1-n-propyl-2- (1-n-propyl-1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate with a yield of 74%, which can be directly put into the next reaction.
In a 100 ml round bottom flask, 1.59 g of 1-n-propyl-2- (1-n-propyl-1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate (5mmol) was weighed in, 20ml of tetrahydrofuran was added and stirred well. 0.99 g of N-bromosuccinimide (5.6mmol) dissolved in 10ml of tetrahydrofuran is then added slowly in an ice-water bath at 0 ℃ and the mixture is stirred completely at room temperature or at 25 ℃ to 50 ℃ for more than 30 minutes until the reaction is complete. After the reaction of the starting materials was completed, the reaction was stopped by pouring the mixture into 20ml of ice water, 20ml of dichloromethane was added, extraction was carried out three times by adding 20ml of water and dichloromethane, the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to give 1.72 g of 1-n-propyl-2- (3-bromo-1-n-propyl-1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate in 87% yield which was directly fed to the next reaction.
In a 100 ml three-necked flask purged with nitrogen, 1.58 g of 1-n-propyl-2- (3-bromo-1-n-propyl-1H-indol-2-yl) -1H-benzo [ d ] are weighed]Imidazole (4mmol) is added with 10ml of new evaporated tetrahydrofuran under the condition of introducing nitrogen and stirred evenly. The mixture was cooled to-78 ℃ with ice, and n-butyllithium (6mmol) was added thereto to conduct a reaction for 0.5 to 2 hours. Then, 0.85 ml of diphenyl phosphine chloride (4.6mmol) and 15 ml of freshly distilled tetrahydrofuran, which had been mixed, were added. Slowly raising the temperature to room temperature for reaction for 12-48 hours. The whole solution is pumped off under reduced pressure, washed twice with a cold ethanol/methanol mixture or purified by column chromatography to obtain 0.2 g of a white powdery pure product 2- (3- (diphenylphosphino) -1-N-propyl-1H-indol-2-yl) -N-N-propyl-benzimidazole,the yield was 10%.1H NMR(400MHz,CDCl3)δ0.59-0.63(m,3H),0.80-0.85(m,3H),1.54-1.94(m,4H),3.76-3.86(m,2H),3.97-4.04(m,1H),4.21-4.28(m,1H),7.16-7.49(m,17H),7.87-7.89(m,1H)。
Example four
An indolylimidazolyl phosphorus ligand is 15- (diphenylphosphino) -7, 8-dihydro-6H-benzo [4',5' ] imidazo [2',1':3,4] [1,4] diaza [1,2-a ] indole with the structure shown in the formula,
the preparation method of the 15- (diphenylphosphino) -7, 8-dihydro-6H-benzo [4',5' ] imidazo [2',1':3,4] [1,4] diaza [1,2-a ] indole comprises the following steps:
in a 250 ml three-necked flask purged with nitrogen, 2.33 g of (1H-indol-2-yl) -1H-benzo [ d ] imidazole (10mmol) was weighed, and 50ml of dimethylformamide was added and stirred uniformly. Then 2.8 g of potassium hydroxide (50mmol) was added and the reaction was stirred thoroughly at room temperature for 2-36 hours, and as most of the potassium hydroxide dissolved, a thick cloudy solution was formed, 1.72 ml of 1, 3-diiodopropane (15mmol) was added and the reaction was allowed to proceed at room temperature for 18-24 hours. After the reaction of the starting materials was completed, the reaction was stopped by spotting, 40 ml of water and 30 ml of dichloromethane were added to the system, and 30 ml of dichloromethane was added three times to extract, and the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase is concentrated and purified by column chromatography to obtain 1.23 g of intermediate of 7, 8-dihydro-6H-benzo [4',5' ] imidazo [2',1':3,4] [1,4] diaza [1,2-a ] indole with 45% yield, which can be directly put into the next step of reaction.
In a 100 ml round bottom flask, 1.37 g of 7, 8-dihydro-6H-benzo [4',5' ] imidazo [2',1':3,4] [1,4] diaza [1,2-a ] indole intermediate (5mmol) was weighed in, 20ml of tetrahydrofuran was added and stirred well. 0.99 g of N-bromosuccinimide (5.6mmol) dissolved in 10ml of tetrahydrofuran is then added slowly in an ice-water bath at 0 ℃ and the mixture is stirred completely at room temperature or at 25 ℃ to 50 ℃ for more than 30 minutes until the reaction is complete. After the reaction of the starting materials was completed, the reaction was stopped by pouring the mixture into 20ml of ice water, 20ml of dichloromethane was added, extraction was carried out three times by adding 20ml of water and dichloromethane, the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to give 1.53 g of the intermediate 15 bromo-7, 8 dihydro-6H-benzo [4',5' ] imidazo [2',1':3,4] [1,4] diaza [1,2-a ] indole in 87% yield which was directly fed to the next step.
In a 100 ml three-necked flask purged with nitrogen, 1.4 g of 15-bromo-7, 8-dihydro-6H-benzo [4',5' were weighed ']Imidazo [2',1':3,4][1,4]Diaza-and [1,2-a ]]Indole (4mmol), adding 10ml of new tetrahydrofuran under nitrogen, and stirring. The mixture was cooled to-78 ℃ with ice, and n-butyllithium (6.4mmol) was added thereto to conduct a reaction for 0.5 to 2 hours. Then, 0.85 ml of diphenyl phosphine chloride (4.6mmol) and 15 ml of freshly distilled tetrahydrofuran, which had been mixed, were added. Slowly raising the temperature to room temperature for reaction for 12-48 hours. All solutions were removed under reduced pressure and washed twice with cold ethanol/methanol mixture or purified by column chromatography to give the pure product 15- (diphenylphosphino) -7, 8-dihydro-6H-benzo [4',5']Imidazo [2',1':3,4][1,4]Diaza-and [1,2-a ]]Indole 0.64 g, yield 35%.1H NMR(400MHz,CDCl3)δ2.53(t,J=6.4Hz,3H)4.28(t,J=6.4Hz,3H)6.90(d,J=8.0Hz,1H),7.00(t,J=8.0Hz,3H),7.25-7.51(m,15H),7.93(d,J=8.0Hz,1H)。
EXAMPLE five
An indolylimidazolyl phosphorus ligand is a 16- (diphenylphosphino) -6,7,8, 9-tetrahydrobenzo [4',5' ] imidazo [2',1':3,4] [1,4] diaza [1,2-a ] indole with the structure shown in the formula,
the preparation method of the 16- (diphenylphosphino) -6,7,8, 9-tetrahydrobenzo [4',5' ] imidazo [2',1':3,4] [1,4] diaza [1,2-a ] indole comprises the following steps:
in a 250 ml three-necked flask purged with nitrogen, 2.33 g of (1H-indol-2-yl) -1H-benzo [ d ] imidazole (10mmol) was weighed, and 50ml of dimethylformamide was added and stirred uniformly. Then 5.32 g of potassium hydroxide (95mmol) were added and the reaction was stirred thoroughly at room temperature for 2-36 hours, and as most of the potassium hydroxide dissolved, a thick cloudy solution was formed, 2.39 ml of 1, 4-dibromobutane (20mmol) was added and the reaction was allowed to proceed at room temperature for 18-24 hours. After the reaction of the starting materials was completed, the reaction was stopped by spotting, 40 ml of water and 30 ml of dichloromethane were added to the system, and 30 ml of dichloromethane was added three times to extract, and the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to give 1.38 g of the intermediate 6,7,8, 9-tetrahydrobenzo [4',5' ] imidazo [2',1':3,4] [1,4] diaza [1,2-a ] indole in 48% yield which was directly fed to the next step.
In a 100 ml round bottom flask, 1.29 g of 6,7,8, 9-tetrahydrobenzo [4',5' ] imidazo [2',1':3,4] [1,4] diaza [1,2-a ] indole (4.5mmol) was weighed in, 20ml of tetrahydrofuran was added and stirred well. 0.85 g of N-bromosuccinimide (4.77mmol) dissolved in 10ml of tetrahydrofuran is then added slowly in an ice-water bath at 0 ℃ and the mixture is stirred completely at room temperature or at 25 ℃ to 50 ℃ for more than 30 minutes until the reaction is complete. After the reaction of the starting materials was completed, the reaction was stopped by pouring the mixture into 20ml of ice water, 20ml of dichloromethane was added, extraction was carried out three times by adding 20ml of water and dichloromethane, the organic phases were combined and dried over anhydrous magnesium sulfate. The 16 bromo-6, 7,8, 9-tetrahydrobenzo [4',5' ] imidazo [2',1':3,4] [1,4] diaza [1,2-a ] indole intermediate is obtained by column chromatography purification, 1.59 g, the yield is 97%, and the intermediate can be directly put into the next reaction.
In a 100 ml three-necked flask purged with nitrogen, 1.46 g of 16-bromo-6, 7,8, 9-tetrahydrobenzo [4',5' were weighed ']Imidazo [2',1':3,4][1,4]Diaza-and [1,2-a ]]Indole (4mmol), adding 10ml of new tetrahydrofuran under nitrogen, and stirring. The mixture was cooled to-78 ℃ with ice, to which was added n-butyllithium (8mmol), and reacted for 0.5 to 2 hours. 1.48 ml of diphenyl phosphonium chloride (8mmol) and 15 ml of freshly distilled tetrahydrofuran, which had been mixed, were then added. Slowly raising the temperature to room temperature for reaction for 12-48 hours. All solutions were removed under reduced pressure, washed twice with cold ethanol/methanol mixture or purified by column chromatography to give the pure product 16- (diphenylphosphino) -6,7,8, 9-tetrahydrobenzo [4',5']Imidazo [2',1':3,4][1,4]Diaza-and [1,2-a ]]Indole 1.04 g, yield55%。1HNMR(400MHz,CDCl3)δ2.10-2.20(m,4H),4.00-4.19(m,4H),7.05-7.41(m,16H),7.72(d,J=8.0Hz,1H),7.88(dd,J=6.4Hz,3.2Hz,1H)。
EXAMPLE six
An indomidazolylphosphine ligand having the structure of 2- (3- (diphenylphosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole shown in table 1 below.
The preparation method of the 2- (3- (diphenylphosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole comprises the following steps:
in a 100 ml three-necked flask evacuated with nitrogen, 1-alkyl-2- (1-alkyl-1H-indol-2-yl) -1H-benzo [ d ] imidazole (8mmol) was weighed, 20ml of freshly distilled tetrahydrofuran was added under nitrogen, and the mixture was stirred uniformly. The mixture was cooled to-78 ℃ with ice, and n-butyllithium (8.8-20mmol) was added thereto to conduct a reaction for 0.5-2 hours. Then, 1.58 ml of diphenyl phosphine chloride (8.8 to 20mmol) and 5 to 20ml of freshly distilled tetrahydrofuran, which had been mixed, were added. Slowly raising the temperature to room temperature for reaction for 12-48 hours. All solutions were pumped off under reduced pressure and washed twice with a cold ethanol/methanol mixture to give the pure product 2- (3- (diphenylphosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole as a white powder, of the formula shown below, in isolated yields as given in table 1 below.
The raw materials, products and separation yields thereof in the preparation process of 2- (3- (diphenylphosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole described in the examples of the present invention are shown in table 1 below.
TABLE 1
EXAMPLE seven
An indomidazolylphosphine ligand having the structure 2- (3- (cyclohexylphosphine) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole shown in table 2 below.
The preparation method of the 2- (3- (cyclohexylphosphine) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole comprises the following steps:
in a 100 ml three-necked flask evacuated with nitrogen, 1-alkyl-2- (1-alkyl-1H-indol-2-yl) -1H-benzo [ d ] imidazole (8mmol) was weighed, 20ml of freshly distilled tetrahydrofuran was added under nitrogen, and the mixture was stirred uniformly. The mixture was cooled to-78 ℃ with ice, and n-butyllithium (8.8-20mmol) was added thereto to conduct a reaction for 0.5-2 hours. Then, 1.58 ml of cyclohexylchlorophosphine (8.8-20mmol) and 5-20 ml of freshly distilled tetrahydrofuran, which had been mixed, were added. Slowly raising the temperature to room temperature for reaction for 12-48 hours. All solutions were pumped off under reduced pressure and washed twice with cold ethanol/methanol mixture to give the pure product 2- (3- (cyclohexylphosphine) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole as a white powder, which is shown in the following reaction scheme, isolated in the following yield as in table 2 below, wherein the 1-alkyl-2- (1-alkyl-1H-indol-2-yl) -1H-benzo [ d ] imidazole was prepared as described in the above examples.
The raw materials, products and isolation yields of the same in the preparation of 2- (3- (cyclohexylphosphine) -N-alkylindol-2-yl) -N-alkyl-benzimidazole are shown in table 2 below.
TABLE 2
Wherein R is1,R2,R4And R5For other alkyl substitution, R3Is a functional group in other disubstituted phosphine chloride, such as phenyl, isopropyl, cyclohexyl, ethyl, tertiary butyl and methyl ethyl. Synthesis of (2-disubstituted phosphinophenyl) -1-alkyl-indole skeleton phosphine ligand from 1-alkyl-2- (1-alkyl-1H-indol-2-yl) -1H-benzo [ d]Starting from imidazole and the corresponding alkyl bromide and disubstituted chlorophosphine, the phases can be selected from the group consisting of example one, example two, example three, example four, example five and example sixSynthesized by the same method.
Example eight: application of 2- (3- (disubstituted phosphino) -N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole phosphine ligand in catalyzing Suzuki cross-coupling reaction.
7-1, several representative catalysts of 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazolephosphine ligands in the examples of the invention, the structures of which are shown in the following formula cat1-3, catalyze Suzuki (Suzuki) cross-coupling reactions.
To a 20mL Schlenk tube, palladium acetate (0.0112 g, 0.05mmol) and phosphine ligand (ratio of palladium to phosphine ligand: 5.0 mol%: 15.0 mol%) were added, a magnetic stir bar equipped with a Teflon coating was added, the system was replaced with nitrogen gas, 5mL of freshly distilled 1, 4-dioxane was added, and the mixture was stirred at room temperature for 10 minutes while stirring to form a palladium complex. In a further Schlenk tube, tripotassium phosphate monohydrate (3.0mmol) and phenylboronic acid (1.5mmol) were added, and after 3 round-trip exchanges of vacuum nitrogen, the required dose of palladium complex solution (example: 1.0 mol% ═ 1.0mL) was drawn off from the stock solution prepared above using a gas-tight syringe into this nitrogen-protected Schlenk tube, 4-chlorotoluene (1.0mmol) was then added with nitrogen, and finally freshly distilled 1, 4-dioxane was added to a total solution portion of 3mL, and stirring was continued for 5 minutes at room temperature after sealing. The Schlenk tube was then placed in a preheated 110 ℃ oil bath for 24 hours. After completion of the reaction, the reaction tube was cooled to room temperature, the reaction was stopped, about 10ml of ethyl acetate and dodecane (1.0mmol) were added to the system, the organic layer was subjected to gas chromatography, and the yield of the identified substance was examined. In the Suzuki cross-coupling reaction, the reaction formula is shown below, and the phosphine ligand and the yield of the catalyst are shown in table 3 below.
TABLE 3
It can be seen from table 3 that various 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazolephosphine ligands catalyze this reaction well.
7-2, 2- (3- (diphenylphosphino) -1-ethyl-1H-indol-2-yl) -N-ethyl-benzimidazole catalyzed cross-coupling reaction of aryl chlorides with arylboronic acids
Low catalytic amount: 0.0025 to 0.02 mol%
To a 50mL Schlenk tube, palladium acetate (0.0045 g, 0.02mmol) and phosphine ligand (the ratio of palladium to phosphine ligand is 2.0 mol%: 6.0 mol%) were added, a magnetic stir bar equipped with a Teflon coating was added, the system was replaced with nitrogen gas, 8mL of freshly distilled 1, 4-dioxane was added, and the mixture was stirred uniformly at room temperature for 10 minutes to form a palladium complex. After 3 cycles of exchange of vacuum nitrogen back and forth in a further Schlenk tube, 0.1mL of the palladium complex solution was drawn off from the stock solution prepared previously by means of a gas-tight syringe into the nitrogen-protected Schlenk tube and freshly distilled 1, 4-dioxane was then added thereto under nitrogen introduction to give a total solution portion of 10 mL.
After a further Schlenk tube was charged with tripotassium phosphate monohydrate (3.0mmol) and arylboronic acid (1.5mmol), the required dose of palladium complex solution (0.0025 mol% 0.1mL or 0.005 mol% 0.2mL or 0.01 mol% 0.4mL or 0.02 mol% 0.8mL) was drawn off from the stock solution prepared before using a gas-tight syringe after 3-cycle exchanges of vacuum nitrogen back and forth to the Schlenk tube protected with nitrogen, then the aryl chloride (1.0mmol) was added with nitrogen, and finally freshly distilled 1, 4-dioxane was added to a total solution portion of 3mL, and stirring was continued at room temperature for 5 minutes after sealing. The Schlenk tube was then placed in a preheated oil bath at 60-120 ℃ for 18-24 hours. After completion of the reaction, the reaction tube was cooled to room temperature, the reaction was stopped, about 10ml of ethyl acetate was added to the system, and the organic layer was subjected to gas chromatography. Then adding about 10ml ethyl acetate for extraction for three to four times respectively, combining organic phases, concentrating under reduced pressure, and performing silica gel column chromatography to obtain the cross-coupling product. Wherein, the reaction formula of the Suzuki (Suzuki) cross-coupling reaction is shown as follows, and the raw materials, the products, the palladium dosage and the separation yield are shown in the following table 4.
TABLE 4
A catalytic amount: 0.1 to 0.6 mol%
Palladium acetate (0.00224 g, 0.01mmol) and phosphine ligand (ratio of palladium to phosphine ligand: 1.0 mol%: 3.0 mol%) were added to a 20mL Schlenk tube, a magnetic stir bar equipped with a Teflon coating was added, the system was replaced with nitrogen, 5mL of freshly distilled 1, 4-dioxane was added, and the mixture was stirred for 10 minutes while adding at room temperature to form a palladium complex.
After a further 20mL Schlenk tube was charged with tripotassium phosphate monohydrate (3.0mmol) and arylboronic acid (1.5mmol), and subsequently after 3 round-trip exchanges of vacuum nitrogen, the required dose of palladium complex solution (0.1 mol% to 0.5mL or 0.2 mol% to 1mL or 0.3 mol% to 1.5mL or a suitable portion thereof) was drawn off from the stock solution prepared before using a gas-tight syringe into the nitrogen-protected Schlenk tube, then the aryl chloride (1.0mmol) was added under nitrogen, and finally freshly distilled 1, 4-dioxane was added to a total solution portion of 3mL, and stirring was continued at room temperature for 5 minutes after sealing. The Schlenk tube was then placed in a preheated oil bath at 60-120 ℃ for 18-24 hours. After completion of the reaction, the reaction tube was cooled to room temperature, the reaction was stopped, about 10ml of ethyl acetate was added to the system, and the organic layer was subjected to gas chromatography. Then, about 10ml of ethyl acetate is added for extraction three to four times, the organic phases are combined, concentrated under reduced pressure and subjected to silica gel column chromatography. Obtaining the cross-coupling product. Wherein, the reaction formula of the Suzuki (Suzuki) cross-coupling reaction is shown as follows, and the raw materials, the products, the palladium dosage and the separation yield are shown as the following 5 serial numbers 1-12.
A catalytic amount: more than 0.6 mol%
Palladium acetate (0.00224 g, 0.01mmol) and phosphine ligand (palladium: phosphine ligand ratio 1.0 mol%: 3.0 mol%) or appropriate portions thereof were added to a 20mL Schlenk tube, a magnetic stir bar equipped with a Teflon coating was added, 1mL of freshly distilled 1, 4-dioxane was added after 3 cycles of back and forth exchange of vacuum nitrogen, and stirring was carried out for 10 minutes with addition at room temperature to form a palladium complex. Potassium phosphate trihydrate (3.0mmol), arylboronic acid (1.5mmol) and aryl chloride (1.0mmol) were then added under nitrogen, and freshly distilled 1, 4-dioxane was added to a total solution volume of 3mL, sealed and stirred at room temperature for 5 minutes. The Schlenk tube was then placed in a preheated oil bath at 60-120 ℃ for 18-24 hours. After completion of the reaction, the reaction tube was cooled to room temperature, the reaction was stopped, about 10ml of ethyl acetate was added to the system, and the organic layer was subjected to gas chromatography. Then, about 10ml of ethyl acetate is added for extraction three to four times, the organic phases are combined, concentrated under reduced pressure and subjected to silica gel column chromatography. Obtaining the cross-coupling product. Wherein, the reaction formula of the Suzuki (Suzuki) cross-coupling reaction is shown as follows, and the raw materials, the products, the palladium dosage and the separation yield are shown as the serial number 13 in the following table 5.
TABLE 5
From the above tables 4 and 5, it can be seen that when the indomidazolylphosphine ligand of the present invention is used in Suzuki cross-coupling reaction, the palladium dosage (mol%) can be greatly reduced to 0.0025-1.0 mol%, even as low as 0.0025 mol%, while the separation yield is ensured.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (7)
1. A method for preparing a phosphine ligand of 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton, comprising the steps of:
dissolving indole-2-carboxylic acid, o-phenylenediamine and sulfuric acid in ethylene glycol, and stirring for 2-36 hours under the condition of heating reflux to obtain a (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate;
dissolving the (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate, sodium hydride or potassium hydroxide in tetrahydrofuran or dimethylformamide, and stirring at 0 ℃ or room temperature for 0.5-2 hours; then adding dimethyl sulfate or alkyl bromide or toluene sulfonic acid alkyl ester, stirring for 2-36 hours at room temperature to obtain 2- (N-alkyl-1H-indole-2-yl) -N-alkyl-benzimidazole;
dissolving the 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole in tetrahydrofuran, adding N-bromosuccinimide at the temperature of 0 ℃ to form a mixture, and stirring the mixture at the temperature of 15-50 ℃ to react for 30 minutes to 4 hours to obtain a 2- (N-alkyl-3-bromo-indol-2-yl) -N-alkyl-benzimidazole intermediate;
dissolving the 2- (N-alkyl-3-bromo-indol-2-yl) -N-alkyl-benzimidazole intermediate in tetrahydrofuran, adding N-butyl lithium, reacting at-75 to-80 ℃ for 0.5 to 2 hours, adding disubstituted chlorophosphine, and reacting at room temperature for 12 to 48 hours to obtain the 2- (3- (disubstituted phosphino) -N-alkyl indol-2-yl) -N-alkyl-benzimidazole phosphine ligand.
2. The method for preparing a phosphine ligand having a 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton according to claim 1, wherein the molar ratio of indole-2-carboxylic acid, o-phenylenediamine and sulfuric acid in the step of preparing the (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate is 1.05-3.0:1.0: 1.05-3.0.
3. The method for preparing a phosphine ligand having a 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton according to claim 1, wherein the molar ratio of the (1H-indol-2-yl) -1H-benzo [ d ] imidazole intermediate, dimethyl sulfate or alkyl bromide or alkyl tosylate, potassium hydroxide or sodium hydride in the step of preparing the 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole is 1.0:3.0-8.0: 3.0-10.0.
4. The method for preparing a phosphine ligand with 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton according to claim 1, wherein the molar ratio of the 2- (N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole to the N-bromosuccinimide is 1.0:1.05-3.0 in the step of preparing the 2- (N-alkyl-3-bromo-indol-2-yl) -N-alkyl-benzimidazole intermediate.
5. The method for preparing a phosphine ligand having a 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton according to claim 1, wherein in the step of preparing the 2- (3- (disubstituted phosphino) -N-alkylindol-2-yl) -N-alkyl-benzimidazolephosphine ligand, the molar ratio of the 2- (N-alkyl-3-bromo-indol-2-yl) -N-alkyl-benzimidazole intermediate, N-butyllithium, and disubstituted chlorophosphine is 1.0:1.1-3.0: 1.1-2.0.
6. Use of the phosphine ligand of 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton prepared by the method according to any one of claims 1 to 5 as a synergist for transition metal catalysts in cross-coupling reactions.
7. The use of the phosphine ligands of 2- (3- (disubstituted phosphino) -N-alkyl-1H-indol-2-yl) -N-alkyl-benzimidazole skeleton according to claim 6, wherein the cross-coupling reaction comprises the reaction of aryl chlorides with organotitanium nucleophiles, suzuki coupling, sabina coupling, polyfluorophenyl arylation, boron coupling, cyanation and α -monoarylation of carbonyl compounds, and/or
The transition metal catalyst is a palladium catalyst.
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Remarkably Effective Phosphanes Simply with a PPh2 moiety:Application to Pd-Catalysed Cross-Coupling Reactions for Tetra- ortho-substituted Biaryl Syntheses;Chau Ming So et al.;《Chemistry a European Journal》;20101231;第7996-8001页 * |
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