CN114907404B - 5- (2- (Disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazolyl phosphine ligand and preparation method and application thereof - Google Patents
5- (2- (Disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazolyl phosphine ligand and preparation method and application thereof Download PDFInfo
- Publication number
- CN114907404B CN114907404B CN202110175011.3A CN202110175011A CN114907404B CN 114907404 B CN114907404 B CN 114907404B CN 202110175011 A CN202110175011 A CN 202110175011A CN 114907404 B CN114907404 B CN 114907404B
- Authority
- CN
- China
- Prior art keywords
- alkyl
- phenyl
- pyrazole
- phosphine ligand
- disubstituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 157
- -1 2- (Disubstituted phosphino) phenyl Chemical group 0.000 title claims abstract description 126
- 239000003446 ligand Substances 0.000 title claims abstract description 93
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 80
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 28
- 150000003624 transition metals Chemical class 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 48
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 30
- 238000006880 cross-coupling reaction Methods 0.000 claims description 27
- 239000003054 catalyst Substances 0.000 claims description 24
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 19
- 238000005859 coupling reaction Methods 0.000 claims description 18
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- REJGOFYVRVIODZ-UHFFFAOYSA-N phosphanium;chloride Chemical class P.Cl REJGOFYVRVIODZ-UHFFFAOYSA-N 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- 229950010765 pivalate Drugs 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- USJRLGNYCQWLPF-UHFFFAOYSA-N chlorophosphane Chemical class ClP USJRLGNYCQWLPF-UHFFFAOYSA-N 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 58
- 229910052763 palladium Inorganic materials 0.000 abstract description 28
- 230000003197 catalytic effect Effects 0.000 abstract description 23
- 125000003118 aryl group Chemical group 0.000 abstract description 18
- 125000003545 alkoxy group Chemical group 0.000 abstract description 12
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 229910052757 nitrogen Inorganic materials 0.000 description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- 239000000543 intermediate Substances 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 239000011248 coating agent Substances 0.000 description 7
- 238000000576 coating method Methods 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 238000003760 magnetic stirring Methods 0.000 description 7
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 7
- 239000004810 polytetrafluoroethylene Substances 0.000 description 7
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 239000007818 Grignard reagent Substances 0.000 description 4
- WDOKISJWRVNYNS-UHFFFAOYSA-N dicyclohexylphosphanium;chloride Chemical compound Cl.C1CCCCC1PC1CCCCC1 WDOKISJWRVNYNS-UHFFFAOYSA-N 0.000 description 4
- 238000004817 gas chromatography Methods 0.000 description 4
- 150000004795 grignard reagents Chemical class 0.000 description 4
- 239000012044 organic layer Substances 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
- QFRIOQZXFIGGLH-UHFFFAOYSA-N 5-(2-bromophenyl)-1-methylpyrazole Chemical compound CN1N=CC=C1C1=CC=CC=C1Br QFRIOQZXFIGGLH-UHFFFAOYSA-N 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- 150000005347 biaryls Chemical group 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- TYLOCIDMZGIHDP-UHFFFAOYSA-N 3,4-dihydronaphthalen-2-yl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC1=Cc2ccccc2CC1 TYLOCIDMZGIHDP-UHFFFAOYSA-N 0.000 description 2
- IMEAVMOWIDGVSY-UHFFFAOYSA-N 5-(2-bromophenyl)-1-phenylpyrazole Chemical compound BrC1=CC=CC=C1C1=CC=NN1C1=CC=CC=C1 IMEAVMOWIDGVSY-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 238000005577 Kumada cross-coupling reaction Methods 0.000 description 2
- 238000006411 Negishi coupling reaction Methods 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- GFRUKEIXCNUFOY-UHFFFAOYSA-N di(propan-2-yl)phosphane;hydrochloride Chemical compound Cl.CC(C)PC(C)C GFRUKEIXCNUFOY-UHFFFAOYSA-N 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 150000002576 ketones Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 150000003003 phosphines Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
- FLNMQGISZVYIIK-UHFFFAOYSA-N 1-ethylpyrazole Chemical compound CCN1C=CC=N1 FLNMQGISZVYIIK-UHFFFAOYSA-N 0.000 description 1
- WITMXBRCQWOZPX-UHFFFAOYSA-N 1-phenylpyrazole Chemical compound C1=CC=NN1C1=CC=CC=C1 WITMXBRCQWOZPX-UHFFFAOYSA-N 0.000 description 1
- ANMVTDVBEDVFRB-UHFFFAOYSA-N 1-propan-2-ylpyrazole Chemical compound CC(C)N1C=CC=N1 ANMVTDVBEDVFRB-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 238000010485 C−C bond formation reaction Methods 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 241000721662 Juniperus Species 0.000 description 1
- 241000274177 Juniperus sabina Species 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- DOWCWUCBOQRQJE-UHFFFAOYSA-N ditert-butylphosphane;hydrochloride Chemical compound Cl.CC(C)(C)PC(C)(C)C DOWCWUCBOQRQJE-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000010651 palladium-catalyzed cross coupling reaction Methods 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- 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
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/65031—Five-membered rings having the nitrogen atoms in the positions 1 and 2
-
- 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
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
-
- 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
- C07C1/325—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 the hetero-atom being a metal atom
- C07C1/326—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 the hetero-atom being a metal atom the hetero-atom being a magnesium atom
-
- 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
-
- 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
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
-
- 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
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole phosphine ligand, a preparation method and application thereof, wherein the phosphine ligand has a structural formula shown in the following formula I: Wherein, R 1 is alkyl or aryl, R 2 is alkyl or aryl, R 3 is hydrogen, alkyl, alkoxy, aryl or fluoro, R 4 is alkyl or aryl, R 5 is hydrogen, alkyl, alkoxy, aryl or fluoro, and R 6 is hydrogen, alkyl, alkoxy, aryl or fluoro. The phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework can form a complex with stable structure with transition metal such as palladium, so that the catalytic activity of the transition metal such as palladium in catalytic reaction is improved, and the phosphine ligand has the advantages of wide application range, good selectivity and mild reaction conditions.
Description
Technical Field
The invention relates to the technical field of organic compounds and synthesis, in particular to a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework, 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. In the field of carbon-carbon bond formation, cross-coupling reactions of Suzuki (Suzuki), juniper mountain (Hiyama), root bank (Negishi), xiong Tian (Kumada), stille (Stille) and the like are common methods for the preparation of alkenyl, biaryl and/or related compounds. Olefins constitute an important structure in valuable natural products, drugs, materials and bioactive agents. Alkenyl halides are a commonly used substrate constituting olefinic compounds, but polysubstituted alkenyl halides are not widely available and their synthesis requires harsh conditions. In contrast, enol ester electrophiles, such as enol sulfonates, carboxylates and carbamates, are readily synthesized from the corresponding carbonyl compounds and contain a wide variety of substituents.
In transition metal catalyzed cross-coupling reactions, ligands play a significant role. In particular, the ligand can effectively regulate the performance of the catalyst, and the coupling reaction is translated into a perfect state. At present, the more commonly used ligands are generally organic phosphine compounds, and the researches on phosphine ligands in the past years show that the minor changes of the positions, the sizes, the steric hindrance, the electrical properties and the like of substituents on a phosphine ligand framework can have important influence on the result of coupling reaction. Among them, well-known phosphine ligands, for example: the Fu, beller, buchwald, hartwig groups all provided excellent catalytic performance in palladium catalyzed cross-coupling reactions.
The phosphine ligand of the pyrazole 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 electrical property of the ligand can be regulated by changing substituent groups on pyrazole and benzene rings; alternatively, the coordination properties of the ligand may be altered by changing the substituents on the phosphorus atoms.
Although multiple types of phosphine ligands have been widely used in coupling reactions, no single or single series of phosphine ligands have heretofore been able to solve all of the problems associated with cross-coupling reactions. The key to solving the coupling bond is to find a suitable catalytic system, especially to find an effective ligand. In coupling reactions of enol ester electrophiles, such as enol carboxylates, particularly low-activity enol carboxylates are highly difficult substrates and have high catalytic activity, so that such reactions have been challenging to date. Therefore, phosphine ligands with high catalytic activity, stable structure and simple synthesis are designed to have a great influence in the reaction.
Disclosure of Invention
In view of the above-mentioned shortcomings of the prior art, the present invention aims to provide a phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton, and a preparation method and application thereof, and aims to solve the problems that the existing phosphine ligand for cross coupling reaction cannot meet the requirements of easy preparation, stable structure and poor catalytic activity when used as a synergist of a transition metal catalyst.
The technical scheme of the invention is as follows:
In a first aspect of the invention, there is provided a phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone, having the structural formula shown in formula I:
Wherein, R 1 is alkyl or aryl, R 2 is alkyl or aryl, R 3 is hydrogen, alkyl, alkoxy, aryl or fluoro, R 4 is alkyl or aryl, R 5 is hydrogen, alkyl, alkoxy, aryl or fluoro, and R 6 is hydrogen, alkyl, alkoxy, aryl or fluoro.
In a second aspect of the present invention, there is provided a process for the preparation of a phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone, comprising the steps of:
reacting 1-alkylpyrazole, n-butyllithium and 1, 2-dibromobenzene to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate; or reacting 1-alkylpyrazole, tert-butyllithium and 1, 2-dibromobenzene to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate;
Reacting the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, n-butyllithium and disubstituted phosphine chloride to obtain a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework; or reacting the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, tert-butyllithium, copper chloride and disubstituted phosphine chloride to obtain the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework.
In a third aspect of the invention there is provided the use of a phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone of the invention as a synergist for a transition metal catalyst in a cross-coupling reaction.
The beneficial effects are that: the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework can form a complex with stable structure with transition metal such as palladium, so that the catalytic activity of the transition metal such as palladium in catalytic reaction is improved, and the phosphine ligand has the advantages of wide application range, good selectivity and mild reaction conditions. The phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework and a transition metal such as palladium form a catalytic system, can prepare various synthetic products such as biaryl and polysubstituted alkenyl compounds, and has great application potential in the synthesis of natural products and pharmaceutical intermediates. The phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework can be widely used for transition metal catalyzed cross coupling Reaction with high difficulty, including Xiong Tian coupling Reaction (Kumada Reaction) and root bank coupling Reaction (Negishi Reaction) of enol pivalate. The catalytic activity amount of the transition metal catalyst such as palladium catalyst can be as low as 0.5mol percent, the separation yield is as high as 95 percent, and the catalyst has profound significance in cross coupling reaction; and simultaneously, the functional groups such as ester, ketone, methoxy and the like are compatible. In addition, the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework has stability to air and moisture and is easy to store; and the space structure and the electrical property of the ligand can be regulated by changing the substituent groups on the pyrazole, so that the coordination performance of the ligand is changed.
The preparation method of the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework 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 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework can be widely used as a synergist of a transition metal catalyst, and is used in cross coupling reaction to form a complex with stable structure together with transition metal such as palladium, so that the catalytic activity of the transition metal such as palladium is improved, and the phosphine ligand can be particularly suitable for Xiong Tian coupling reaction and root-bank coupling reaction of high-difficulty enol pivalate, the catalytic activity of the transition metal catalyst such as palladium catalyst can be as low as 0.5mol percent, and the separation yield is as high as 95 percent.
Detailed Description
The invention provides a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework, a preparation method and application thereof, and further detailed description of the invention is provided below for the purpose, technical scheme and effect of the invention to be clearer and clearer. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The embodiment of the invention provides a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework, which has the structure shown in the following formula I:
Wherein, R 1 is alkyl or aryl, R 2 is alkyl or aryl, R 3 is hydrogen, alkyl, alkoxy, aryl or fluorine, R 4 is alkyl or aryl, R 5 is hydrogen, alkyl, alkoxy, aryl or fluorine, and R 6 is hydrogen, alkyl, alkoxy, aryl or fluorine.
In the above structural formula I, it is particularly preferable that R 1 is one of phenyl, ethyl, isopropyl, tert-butyl, 1-adamantyl, cyclopentyl, cyclohexyl, o-tolyl, p-methoxyphenyl, p-fluorophenyl, p-trifluoromethylphenyl, 3, 5-dimethylphenyl, 3, 5-bis (trifluoromethyl) phenyl, and 1-naphthyl; r 2 is one of phenyl, ethyl, isopropyl, tert-butyl, 1-adamantyl, cyclopentyl, cyclohexyl, o-tolyl, p-methoxyphenyl, p-fluorophenyl, p-trifluoromethylphenyl, 3, 5-dimethylphenyl, 3, 5-di (trifluoromethyl) phenyl and 1-naphthyl; r 3 is one of hydrogen, C1-10 alkyl, C1-10 alkoxy, phenyl, fluorine and trifluoromethyl; r 4 is one of C1-C10 alkyl, C3-C10 cycloalkyl, oxygen heterocycle, epoxy alkyl, alkoxy alkyl, oxygen heterocyclic group and phenyl; r 5 is one of hydrogen, C1-10 alkyl, C1-10 alkoxy, phenyl, fluorine and trifluoromethyl; r 6 is one of hydrogen, C1-10 alkyl, C1-10 alkoxy, phenyl, fluorine and trifluoromethyl.
Still further, in the R 3, the C1-C10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-C10 alkyl groups, and the C1-C10 alkoxy group includes methoxy, ethoxy, n-propoxy, isopropoxy and C4-C10 alkoxy groups;
In the R 4, the C1-C10 alkyl group comprises methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-C10 alkyl groups, the C3-C10 cycloalkyl group comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C7-C10 cycloalkyl groups, the oxacycle comprises tetrahydrofuran, the alkylene oxide comprises propylene oxide, the alkoxyalkyl group comprises methoxymethyl, and the oxacycloalkyl group comprises tetrahydrofuranmethyl;
In the R 5, the C1-C10 alkyl group comprises methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-10 alkyl group, and the C1-C10 alkoxy group comprises methoxy, ethoxy, n-propoxy, isopropoxy and C4-C10 alkoxy group;
In the R 6, the C1-C10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-10 alkyl group, and the C1-C10 alkoxy group includes methoxy, ethoxy, n-propoxy, isopropoxy and C4-C10 alkoxy group.
The phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework in the preferred situation can be combined with transition metal such as palladium to obtain a catalytic system with better catalytic effect, so as to prepare various synthetic products such as polysubstituted olefin compounds.
The phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework provided by the embodiment of the invention can form a complex with stable structure with transition metal such as palladium, so that the catalytic activity of the transition metal such as palladium in catalytic reaction is improved, and the phosphine ligand has the advantages of wide application range, good selectivity and mild reaction conditions. The phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework and a transition metal such as palladium form a catalytic system, can prepare various synthetic products such as biaryl and polysubstituted olefin compounds, and has great application potential in the synthesis of natural products and pharmaceutical intermediates. The phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework provided by the embodiment of the invention can be suitable for transition metal-catalyzed cross-coupling reactions with high difficulty, such as Xiong Tian cross-coupling Reaction (Kumada Reaction) and root-bank cross-coupling Reaction (Negishi Reaction) of enol pivalate. The catalytic activity amount of the transition metal catalyst such as palladium catalyst can be as low as 0.5mol percent, the separation yield is as high as 95 percent, and the catalyst has profound significance in cross coupling reaction; and simultaneously, the functional groups such as ester, ketone, methoxy and the like are compatible. In addition, the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework disclosed by the embodiment of the invention has stability to air and moisture and is easy to store; and the space structure and the electrical property of the ligand can be regulated by changing the substituent groups on the pyrazole, so that the coordination performance of the ligand is changed.
The embodiment of the invention provides a preparation method of a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework, which comprises the following steps:
reacting 1-alkylpyrazole, n-butyllithium and 1, 2-dibromobenzene to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate; or reacting 1-alkylpyrazole, tert-butyllithium and 1, 2-dibromobenzene to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate;
Reacting the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, n-butyllithium and disubstituted phosphine chloride to obtain a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework; or reacting the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, tert-butyllithium, copper chloride and disubstituted phosphine chloride to obtain the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework.
As a specific example, the preparation method of the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework comprises the following steps:
s01, dissolving 1-alkylpyrazole in a solvent (such as tetrahydrofuran), adding n-butyllithium at the temperature of 0 ℃, uniformly stirring for 2 hours, then adding 1, 2-dibromobenzene, and reacting for 2-24 hours at room temperature to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate; or dissolving 1-alkylpyrazole in tetrahydrofuran, adding tert-butyllithium at-75 to-80 ℃, more preferably-78 ℃, and reacting for 1 hour at room temperature. Then adding 1, 2-dibromobenzene at 0 ℃ to react for 2-24 hours at room temperature to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate;
S02, dissolving the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate in tetrahydrofuran, adding n-butyllithium at a temperature of-75 to 80 ℃ and more preferably at a temperature of-78 ℃ for uniformly stirring for 20 to 30 minutes, then adding disubstituted phosphine chloride, and reacting at room temperature for 12 to 24 hours to obtain a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton; or dissolving 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate in toluene, adding tert-butyllithium at-75-80deg.C, more preferably-78deg.C, and stirring for 1 hr. Copper chloride was then added and reacted for 15 minutes. Then adding disubstituted phosphine chloride, and reacting at room temperature until the color of the mixture changes after the reaction. Then reacting at 140 ℃ for 16-24 hours to obtain the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework.
Specifically, in the above step S01, as a specific example, the reaction formula for preparing the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate is as follows:
In order to obtain a better reaction effect, the molar ratio of the 1-alkylpyrazole, the n-butyllithium and the 1, 2-dibromobenzene is preferably 1.0 (1.0-1.02): 1.0-1.02. Further preferably, the 1-alkylpyrazole is dissolved in tetrahydrofuran, n-butyllithium is added at a ratio of 1.0 (1.0-1.02) at a temperature of 0 ℃, and the mixture is stirred uniformly for 2 hours; 1, 2-dibromobenzene was then added in a ratio of 1.0 (1.0-1.02) and reacted at room temperature for 2 hours.
Further preferably, after the thin layer chromatography detection substrate is completely consumed, adding water to stop the reaction, adding ethyl acetate for extraction and separation; the organic phase is concentrated after drying over sodium sulfate and purified by column chromatography to give the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate.
It is noted that the preparation of the examples of the present invention also makes it possible to set the molar ratio of 1-alkylpyrazole, tert-butyllithium and 1, 2-dibromobenzene to 1.0:1.0. Further preferably, the 1-alkylpyrazole is dissolved in tetrahydrofuran, tert-butyllithium is added at-75 to 80 ℃, more preferably at-78 ℃ in a ratio of 1.0:1.0, and reacted at room temperature for 2 hours; 1, 2-dibromobenzene was then added in a ratio of 1.0:1.0 and reacted at room temperature for 2-24 hours.
Further preferably, after the thin layer chromatography detection substrate is completely consumed, adding water to stop the reaction, adding ethyl acetate for extraction and separation; the organic phase was concentrated after drying over sodium sulfate and purified by column chromatography to give the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate as shown in the following equation:
In the step S02, as a preferred example, in the step of preparing the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton, the molar ratio of the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, n-butyllithium and disubstituted chlorophosphine is 1.0:1.1 (1.1-1.2). Further preferably, the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate is dissolved in tetrahydrofuran, and n-butyllithium is added at a ratio of 1.0:1.1 at-75 to 80 ℃, more preferably-78 ℃, and uniformly stirred for 20 to 30 minutes; subsequently, the disubstituted chlorophosphine is added in the proportion of 1.0 (1.1-1.2), and the reaction is stirred at room temperature for 12-24 hours. The reaction formula of S02 is shown below:
Further preferably, after the reaction is completed, all solvents are removed under reduced pressure, and the mixture is washed three times with cold methanol to obtain powdery phosphine ligands of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton.
It is noted that the preparation of the embodiment of the invention can also lead the mol ratio of the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, the tertiary butyl lithium, the copper chloride and the disubstituted chlorophosphine to be 1.0:2.0:1.0:1.2. Dissolving 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate in toluene, adding 1.0:2.0 ratio of tert-butyllithium at-75-80deg.C, more preferably-78deg.C, and stirring uniformly for 1 hr; copper chloride was then added in a 1.0:1.0 ratio and reacted for 15 minutes. Then, the disubstituted phosphine chloride was added in a ratio of 1.0:1.2, and reacted at room temperature until the color of the mixture changed. Then reacting at 140 ℃ for 16-24 hours to obtain the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework, wherein the reaction formula is shown as follows:
Further preferably, ethyl acetate is added after the thin layer chromatography detection substrate is completely consumed, 30% ammonia water is added for extraction, separation and repeated extraction until the color of the organic phase becomes colorless; the organic phase is concentrated after drying over sodium sulfate and purified by column chromatography to give the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone as a powder.
The preparation method of the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework 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 the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton as a synergist of a transition metal catalyst in cross coupling reaction.
Wherein the cross-coupling reaction includes, but is not limited to Xiong Tian coupling reactions, root-bank coupling reactions, suzuki coupling reactions, sabina coupling reactions, boron-based coupling reactions, and cyanidation reactions.
Preferably, the transition metal catalyst is a palladium catalyst.
The phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework provided by the embodiment of the invention can be widely used as a synergist of a transition metal catalyst, and is used for forming a complex with stable structure with transition metal such as palladium in cross coupling reaction, so that the catalytic activity of the transition metal such as palladium in catalytic reaction is improved, and the phosphine ligand can be particularly suitable for use in high-difficulty Xiong Tianhe-bank coupling reaction of enol pivalate, the catalytic activity of the transition metal catalyst such as palladium catalyst can be as low as 0.5mol percent, and the separation yield is as high as 95 percent.
In the embodiment of the invention, the room temperature refers to the room temperature of 10-30 ℃.
The invention is further illustrated by the following specific examples.
Example 1: synthesis of 5- (2- (dicyclohexylphosphino) phenyl) -1-methyl-1H-pyrazole
In a 100 ml two-necked flask, 0.886 g of 1-methylpyrazole (10.8 mmol) was weighed. After 3 times of nitrogen exchange, 30 ml of freshly distilled tetrahydrofuran was added under nitrogen and stirred uniformly. After the mixture was cooled to 0 ℃, n-butyllithium (11.0 mmol) was then added dropwise and reacted for 2 hours. 1.3 ml of 1, 2-dibromobenzene (11.0 mmol) was then added dropwise. The reaction was allowed to proceed at room temperature for 2 hours. Then, 20ml of water was added to the system, and 100 ml of ethyl acetate was added three times to extract each, and the organic phases were combined and dried over anhydrous sodium sulfate. After all the solution was removed under reduced pressure, the concentrated reaction mixture was purified by column chromatography to give 0.73 g of 5- (2-bromophenyl) -1-methyl-1H-pyrazole intermediate as a yellow powder, yield 29％.1H NMR(400MHz,CDCl3)δ7.70–7.67(m,1H),7.53(d,J＝1.7Hz,1H),7.41–7.37(m,1H),7.31–7.28(m,2H),6.26(d,J＝1.7Hz,1H),3.71(s,3H).
In a 100 ml two-necked flask, 0.907 g of 5- (2-bromophenyl) -1-methyl-1H-pyrazole (3.825 mmol) was weighed into. After 3 times of nitrogen exchange, 40 ml of freshly distilled tetrahydrofuran was added under nitrogen and stirred uniformly. After the mixture was cooled to-78 ℃, n-butyllithium (4.2 mmol) was then added dropwise and reacted for 20 minutes. Then 1.0 ml dicyclohexylphosphine chloride (4.59 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 20 hours. After all the solutions were removed under reduced pressure, they were washed three times with cold methanol to give 0.51 g of pure product 5- (2- (dicyclohexylphosphino) phenyl) -1-methyl-1H-pyrazole as a white powder in yield 37％.1H NMR(400MHz,CDCl3)δ7.60–7.58(m,1H),7.50(s,1H),7.46–7.37(m,2H),7.26–7.24(m,1H),6.17(s,1H),3.62(s,3H),1.87–1.80(m,2H),1.70–1.55(m,10H),1.25–1.03(m,10H).
Example 2: synthesis of 5- (2- (diisopropylphosphino) phenyl) -1-methyl-1H-pyrazole
In a 100 ml two-necked flask, 0.696 g of 5- (2-bromophenyl) -1-methyl-1H-pyrazole (2.90 mmol) was weighed out. After 3 times of nitrogen exchange, 40 ml of freshly distilled tetrahydrofuran was added under nitrogen and stirred uniformly. After the mixture was cooled to-78 ℃, n-butyllithium (3.2 mmol) was then added dropwise and reacted for 20 minutes. Then, 0.55 ml of diisopropylphosphine chloride (3.50 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 24 hours. After all the solutions were removed under reduced pressure, they were washed three times with cold methanol to give 0.60 g of pure product 5- (2- (diisopropylphosphino) phenyl) -1-methyl-1H-pyrazole as a white powder in yield 75％.1H NMR(400MHz,CDCl3)δ7.60–7.57(m,1H),7.50(d,J＝1.8Hz,1H),7.46–7.37(m,2H),7.28–7.25(m,1H),6.17(d,J＝1.8Hz,1H),3.64(s,3H),2.08–2.02(m,2H),1.03–0.98(m,6H),0.94–0.89(m,6H).
Example 3: synthesis of 5- (2- (dicyclohexylphosphino) phenyl) -1-ethyl-1H-pyrazole
In a 100ml two-necked flask, 2.4 g of 1-ethylpyrazole (25.0 mmol) was weighed. After 3 times of nitrogen exchange, 40ml of freshly distilled tetrahydrofuran was added under nitrogen and stirred uniformly. After the mixture was cooled to 0 ℃, n-butyllithium (25.0 mmol) was then added dropwise and reacted for 2 hours. Then, 3.0 ml of 1, 2-dibromobenzene (25.0 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 2 hours. Then, 20ml of water was added to the system, and 100ml of ethyl acetate was added three times to extract each, and the organic phases were combined and dried over anhydrous sodium sulfate. After all the solution was removed under reduced pressure, the concentrated reaction mixture was purified by column chromatography to give 1.88 g of 5- (2-bromophenyl) -1-ethyl-1H-pyrazole intermediate as an orange liquid product in yield 30％.1H NMR(400MHz,CDCl3)δ7.70–7.68(m,1H),7.57(d,J＝1.8Hz,1H),7.41–7.37(m,1H),7.32–7.28(m,2H),6.24(d,J＝1.8Hz,1H),3.97(q,J＝7.2Hz,2H),1.34(t,J＝7.2Hz,3H).
In a 100ml two-necked flask, 0.753 g of 5- (2-bromophenyl) -1-ethyl-1H-pyrazole (3.0 mmol) was weighed. After 3 times of nitrogen exchange, 30ml of freshly distilled tetrahydrofuran was added under nitrogen and stirred uniformly. After the mixture was cooled to-78 ℃, n-butyllithium (3.3 mmol) was then added dropwise and reacted for 20 minutes. Then, 0.73 ml of dicyclohexylphosphine chloride (3.3 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 18-24 hours. After all the solution was taken off under reduced pressure, it was washed three times with cold methanol to give 0.17 g of pure product 5- (2- (dicyclohexylphosphino) phenyl) -1-ethyl-1H-pyrazole as a white powder in yield 16％.1H NMR(400MHz,CDCl3)δ7.60–7.58(m,1H),7.54(d,J＝1.8Hz,1H),7.46–7.37(m,2H),7.28–7.25(m,1H),6.15(d,J＝1.8Hz,1H),3.88(q,J＝7.2Hz,2H),1.83–1.54(m,12H),1.33(t,J＝7.2Hz,3H),1.26–0.99(m,10H).
Example 4: synthesis of 5- (2- (dicyclohexylphosphino) phenyl) -1-isopropyl-1H-pyrazole
In a 100 ml two-necked flask, 3.3 g of 1-isopropylpyrazole (30.0 mmol) was weighed. After 3 times of nitrogen exchange, 40 ml of freshly distilled tetrahydrofuran was added under nitrogen and stirred uniformly. After the mixture was cooled to-78 ℃, t-butyllithium (30.0 mmol) was then added dropwise, and the reaction was carried out at room temperature for 1 hour. The mixture was then cooled to 0℃and 3.6 ml of 1, 2-dibromobenzene (29.7 mmol) were then added dropwise. The reaction was allowed to proceed at room temperature for 2 hours. Then, 20ml of water was added to the system, and 100 ml of ethyl acetate was added three times to extract each, and the organic phases were combined and dried over anhydrous sodium sulfate. After all the solution was removed under reduced pressure, the concentrated reaction mixture was purified by column chromatography to give 2.72 g of 5- (2-bromophenyl) -1-isopropyl-1H-pyrazole intermediate as a yellow powder in yield 34％.1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.0Hz,1H),7.60(d,J＝1.4Hz,1H),7.41–7.37(m,1H),7.33–7.28(m,2H),6.21(d,J＝1.7Hz,1H),4.20–4.10(m,1H),1.43(br,6H).
In a 100 ml two-necked flask, 0.753 g of 5- (2-bromophenyl) -1-isopropyl-1H-pyrazole (3.0 mmol) was weighed. After 3 times of nitrogen exchange, 30 ml of freshly distilled tetrahydrofuran was added under nitrogen and stirred uniformly. After the mixture was cooled to-78 ℃, n-butyllithium (3.3 mmol) was then added dropwise and reacted for 20 minutes. Then, 0.73 ml of dicyclohexylphosphine chloride (3.3 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 18 hours. After all the solutions were removed under reduced pressure, they were washed three times with cold methanol to give 0.57 g of pure product 5- (2- (dicyclohexylphosphino) phenyl) -1-isopropyl-1H-pyrazole as a white powder in yield 50％.1H NMR(400MHz,CDCl3)δ7.61–7.58(m,1H),7.56(d,J＝1.6Hz,1H),7.45–7.36(m,2H),7.26–7.23(m,1H),6.12(d,J＝1.7Hz,1H),4.11–4.01(m,1H),1.74–1.46(m,15H),1.31–0.97(m,13H).
Example 5: synthesis of 5- (2- (diisopropylphosphino) phenyl) -1-isopropyl-1H-pyrazole
In a 100ml two-necked flask, 0.795 g of 5- (2-bromophenyl) -1-isopropyl-1H-pyrazole (3.0 mmol) was weighed. After 3 times of nitrogen exchange, 30ml of freshly distilled tetrahydrofuran was added under nitrogen and stirred uniformly. After the mixture was cooled to-78 ℃, n-butyllithium (3.3 mmol) was then added dropwise and reacted for 20 minutes. Then, 0.53 ml of diisopropylphosphine chloride (3.3 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 18 hours. After all the solutions were removed under reduced pressure, they were washed three times with cold methanol to give 0.72 g of pure 5- (2- (diisopropylphosphino) phenyl) -1-isopropyl-1H-pyrazole as a pale yellow powder in yield 80％.1H NMR(400MHz,CDCl3)δ7.60–7.57(m,2H),7.46–7.36(m,2H),7.27–7.24(m,1H),6.13(d,J＝1.7Hz,1H),4.13–4.03(m,1H),2.21(s,1H),1.89(s,1H),1.52(s,3H),1.32(s,3H),1.09–0.89(m,12H).
Example 6: synthesis of 5- (2- (di-tert-butylphosphino) phenyl) -1-isopropyl-1H-pyrazole
In a 50 ml Schlenk tube, 0.665 g of 5- (2-bromophenyl) -1-isopropyl-1H-pyrazole (2.5 mmol) was weighed in. After 3 times of nitrogen exchange, 20ml of freshly distilled toluene was added under nitrogen and stirred uniformly. After the mixture was cooled to-78 ℃, t-butyllithium (5.0 mmol) was then added dropwise and reacted for 1 hour. Then, 0.248 g of copper chloride (2.5 mmol) was added and the reaction was carried out for 15 minutes. Then, 0.57 ml of di-t-butylphosphine chloride (3.0 mmol) was added dropwise. The reaction was stirred at room temperature until the color of the mixture changed. The Schlenk tube was then placed in an oil bath preheated to 140 ℃ for 16 hours. After the completion of the reaction, the reaction tube was cooled to room temperature, the reaction was stopped, ethyl acetate (50.0 mL) was added to the system, and 50 mL of 30% aqueous ammonia was added to each of the mixture for extraction several times until the color of the organic phase became colorless, and the organic phases were combined and dried over anhydrous sodium sulfate. After all the solution was removed under reduced pressure, the concentrated reaction mixture was purified by column chromatography to give 0.53 g of pure product 5- (2- (di-t-butylphosphino) phenyl) -1-isopropyl-1H-pyrazole as a white powder in yield 65％.1H NMR(400MHz,CDCl3)δ7.91–7.89(m,1H),7.55(d,J＝1.6Hz,1H),7.43–7.37(m,2H),7.24–7.21(m,1H),6.09(d,J＝1.8Hz,1H),4.16–4.06(m,1H),1.55(d,J＝5.1Hz,3H),1.32(d,J＝5.2Hz,3H),1.22–1.10(m,18H).
Example 7: synthesis of 5- (2- (dicyclohexylphosphino) phenyl) -1-phenyl-1H-pyrazole
In a 100ml two-necked flask, 1.44 g of 1-phenylpyrazole (10.0 mmol) was weighed. After 3 times of nitrogen exchange, 40 ml of freshly distilled tetrahydrofuran was added under nitrogen and stirred uniformly. After the mixture was cooled to-78 ℃, t-butyllithium (10.0 mmol) was then added dropwise, and the reaction was carried out at room temperature for 1 hour. The mixture was then cooled to 0℃and 1.2 ml of 1, 2-dibromobenzene (10.0 mmol) was then added dropwise. The reaction was allowed to proceed at room temperature for 2 hours. Then, 20ml of water was added to the system, and 100ml of ethyl acetate was added three times to extract each, and the organic phases were combined and dried over anhydrous sodium sulfate. After all the solution was removed under reduced pressure, the concentrated reaction mixture was purified by column chromatography to give 0.69 g of 5- (2-bromophenyl) -1-phenyl-1H-pyrazole intermediate as a yellow powder, yield 23％.1H NMR(400MHz,CDCl3)δ7.76(d,J＝1.8Hz,1H),7.60–7.58(m,1H),7.31–7.20(m,8H),6.51(d,J＝1.8Hz,1H).
In a 100 ml two-necked flask, 0.349 g of 5- (2-bromophenyl) -1-phenyl-1H-pyrazole (1.167 mmol) was weighed. After 3 times of nitrogen exchange, 20 ml of freshly distilled tetrahydrofuran was added under nitrogen and stirred uniformly. After the mixture was cooled to-78 ℃, n-butyllithium (1.3 mmol) was then added dropwise and reacted for 20 minutes. Then, 0.29 ml of dicyclohexylphosphine chloride (1.3 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 18 hours. After all the solutions were removed under reduced pressure, they were washed three times with cold methanol to give 0.27 g of pure product 5- (2- (dicyclohexylphosphino) phenyl) -1-phenyl-1H-pyrazole as yellow powder in yield 56％.1H NMR(400MHz,CDCl3)δ7.71(d,J＝7.8Hz,1H),7.47–7.37(m,4H),7.24–7.09(m,5H),6.36(d,J＝7.8Hz,1H),1.68–1.49(m,11H),1.25–0.88(m,11H).
In addition, 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazoles shown in Table 1 below can be prepared by reference to the procedure described in the following schemes.
TABLE 1
Example 8: use of a phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone in palladium-catalyzed enol pivalate Xiong Tian (Kumada) cross-coupling reactions and root-bank cross-coupling reactions.
Several catalysts of phosphine ligands of example 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone of the present invention, having the structure shown below in formulas cat1-7, catalyze Xiong Tian (Kumada) cross-coupling reactions:
There was a step of adding triethylamine palladium acetate (0.0018 g, 0.008 mmol) and a magnetic stirring bar equipped with a polytetrafluoroethylene coating were placed in a 20mL Schlenk tube, the system was replaced with nitrogen protection, then 0.8mL of freshly distilled tetrahydrofuran was added, and they were stirred uniformly for 1 minute. Simultaneously, phosphine ligand (palladium: phosphine ligand ratio 2.0mol%:2 mol%) and a magnetic stirring bar equipped with a polytetrafluoroethylene coating were placed in another 20mL Schlenk tube. After 3 nitrogen exchanges, the corresponding amounts (e.g., 0.4mL,2.0 mol%) and triethylamine (0.05 mL) were withdrawn into a Schlenk tube, which had been charged with phosphine ligand and protected by nitrogen, using a gas-tight syringe in a stock palladium solution. The solution of palladium complex is heated for about 1 to 2 minutes until the solvent begins to boil and stirred at room temperature for 5 minutes. Subsequently 3, 4-dihydronaphthalen-2-yl pivalate (0.2 mmol) and grignard reagent in tetrahydrofuran (0.4 mmol) were added under nitrogen. The Schlenk tube was then left to react at room temperature for 10 minutes. Ethyl acetate (4.0 mL) and water (2.0 mL) were then added to the system, and the extracted organic layer was then subjected to gas chromatography and examined to determine the yield of the coupled product.
Step of adding no triethylamine Palladium acetate (0.0018 g, 0.008 mmol), phosphine ligand (Palladium: phosphine ligand ratio 4.0mol%:4 mol%) and magnetic stirring bar equipped with polytetrafluoroethylene coating were placed in a 20mL Schlenk tube, the system was replaced with nitrogen gas, then 0.8mL freshly distilled tetrahydrofuran was added, and they were stirred uniformly for 1 minute to form palladium complex. Simultaneously, a magnetic stirring rod equipped with a polytetrafluoroethylene coating was placed in another 20mL Schlenk tube. After 3 nitrogen exchanges, the corresponding amount (e.g., 0.4mL,2.0 mol%) was withdrawn into a nitrogen-protected Schlenk tube using a gas-tight syringe in a stock palladium complex solution. The solution of palladium complex is heated for about 1 to 2 minutes until the solvent begins to boil and stirred at room temperature for 5 minutes. Subsequently 3, 4-dihydronaphthalen-2-yl pivalate (0.2 mmol) and grignard reagent in tetrahydrofuran (0.4 mmol) were added under nitrogen. The Schlenk tube was then left to react at room temperature for 10 minutes. Ethyl acetate (4.0 mL) and water (2.0 mL) were then added to the system, and the extracted organic layer was then subjected to gas chromatography and examined to determine the yield of the coupled product.
/>
Wherein, in the above-mentioned catalytic Xiong Tian cross-coupling reaction, the phosphine ligand of the catalyst and the yield are shown in the following table 2.
TABLE 2
As can be seen from Table 2, the phosphine ligands of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole frameworks described above can exhibit excellent catalytic performance in the Xiong Tian coupling reaction described above and have better catalytic efficiency than other commercially available ligands.
8.2, 5- (2- (Dicyclohexylphosphino) phenyl) -1-isopropyl-1H-pyrazole catalyzed Xiong Tian Cross-coupling reaction of enolpivalate
Palladium acetate (0.0018 g, 0.008 mmol), phosphine ligand (palladium: phosphine ligand ratio 4.0mol%:4-16 mol%), and enolpivalate (0.2 mmol, if solid) and a magnetic stirring bar equipped with a polytetrafluoroethylene coating were placed in a 20mL Schlenk tube. After 3 nitrogen exchanges, enol pivalate (0.2 mmol, if liquid) and freshly distilled tetrahydrofuran (0.4 mL) and grignard reagent in tetrahydrofuran (0.4 mmol) were added under nitrogen. The Schlenk tube was then placed in an oil bath at room temperature or preheated to 50℃or 110℃for 1-24 hours, as shown below. After the completion of the reaction, the reaction tube was cooled to room temperature, the reaction was stopped, ethyl acetate (4.0 mL) and water (2.0 mL) were added to the system, and then the extracted organic layer was subjected to gas chromatography. Thereafter, about 10mL of ethyl acetate was added three to four times each for extraction, and the organic phases were combined. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to give the cross-coupled product.
Wherein, in the above-mentioned catalytic Xiong Tian cross-coupling reaction, the palladium amount, the catalyst phosphine ligand and the yield are shown in the following table 3.
TABLE 3 Table 3
/>
8.3, Root-shore Cross-coupling reaction of 5- (2- (dicyclohexylphosphino) phenyl) -1-isopropyl-1H-pyrazole catalyzed enol pivalate
A magnetic stirring bar equipped with a polytetrafluoroethylene coating was placed in a 20mL Schlenk tube, the system was replaced with nitrogen, then zinc chloride (0.4 mmol) in tetrahydrofuran as a solvent was added, and it was stirred at 0℃for 1 minute. Then, a Grignard reagent (0.8 mmol) in tetrahydrofuran as a solvent was added and stirred at room temperature for 30 minutes, thereby obtaining an organozinc reagent.
Palladium acetate (0.0018 g, 0.008 mmol), phosphine ligand (palladium: phosphine ligand ratio 4.0mol%:4.0 mol%), and enolpivalate (0.2 mmol, if solid) and a magnetic stirring bar equipped with a polytetrafluoroethylene coating were placed in another 20mL Schlenk tube. After 3 nitrogen exchanges, enol pivalate (0.2 mmol, if liquid) was added under nitrogen, freshly distilled tetrahydrofuran (0.4 mL) and freshly prepared organozinc reagent. The Schlenk tube was then left to react at room temperature for 4-6 hours as shown below. After the completion of the reaction, the reaction tube was cooled to room temperature, the reaction was stopped, ethyl acetate (4.0 mL) and water (2.0 mL) were added to the system, and then the extracted organic layer was subjected to gas chromatography. Thereafter, about 10mL of ethyl acetate was added three to four times each for extraction, and the organic phases were combined. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to give the cross-coupled product.
Wherein, in the above-mentioned catalytic root cross-coupling reaction, the palladium amount, the catalyst phosphine ligand and the yield are shown in the following table 4.
TABLE 4 Table 4
As is clear from tables 3 and 4 above, using the phosphine ligand of example 5- (2- (dicyclohexylphosphino) phenyl) -1-isopropyl-1H-pyrazole backbone of the present invention for the first palladium-catalyzed Xiong Tianhe-shore cross-coupling reaction of enol pivalate can greatly reduce the palladium usage (mol%) to between 0.5 and 4.0 with a separation yield of 95%, even at room temperature.
It is to be understood that the invention is not limited in its application to the examples described above, but is capable of modification and variation in light of the above teachings by those skilled in the art, and that all such modifications and variations are intended to be included within the scope of the appended claims.
Claims (8)
1. A phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework, which is characterized in that the structural formula is shown in the formula I:
Wherein, R 1 is one of phenyl, ethyl, isopropyl, tertiary butyl, 1-adamantyl, cyclopentyl, cyclohexyl, o-tolyl, p-methoxyphenyl, p-fluorophenyl, p-trifluoromethylphenyl, 3, 5-dimethylphenyl, 3, 5-di (trifluoromethyl) phenyl and 1-naphthyl; r 2 is one of phenyl, ethyl, isopropyl, tert-butyl, 1-adamantyl, cyclopentyl, cyclohexyl, o-tolyl, p-methoxyphenyl, p-fluorophenyl, p-trifluoromethylphenyl, 3, 5-dimethylphenyl, 3, 5-di (trifluoromethyl) phenyl and 1-naphthyl; r 3 is one of hydrogen, C1-C10 alkyl, phenyl, fluorine and trifluoromethyl; r 4 is one of C1-C10 alkyl, C3-C10 cycloalkyl and phenyl; r 5 is one of hydrogen, C1-C10 alkyl, phenyl, fluorine and trifluoromethyl; r 6 is one of hydrogen, C1-C10 alkyl, phenyl, fluorine and trifluoromethyl.
2. The phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone according to claim 1, wherein in R 3, the C1-C10 alkyl is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-C10 alkyl;
In the R 4, the alkyl of the C1-C10 is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and alkyl of the C5-C10, and the cycloalkyl of the C3-C10 is one of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloalkyl of the C7-C10;
In the R 5, the C1-C10 alkyl is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-C10 alkyl;
In the R 6, the C1-C10 alkyl is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-C10 alkyl.
3. A process for the preparation of a phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone according to any one of claims 1 to 2, comprising the steps of:
reacting 1-alkylpyrazole, n-butyllithium and 1, 2-dibromobenzene to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate; or reacting 1-alkylpyrazole, tert-butyllithium and 1, 2-dibromobenzene to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate;
Reacting the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, n-butyllithium and disubstituted phosphine chloride to obtain a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework; or reacting the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, tert-butyllithium, copper chloride and disubstituted phosphine chloride to obtain the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework.
4. A process for the preparation of a phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone according to claim 3, comprising the steps of:
Dissolving 1-alkylpyrazole in a solvent, adding n-butyllithium at 0 ℃, stirring for 2 hours, then adding 1, 2-dibromobenzene, and reacting for 2-24 hours to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate; or dissolving 1-alkylpyrazole in a solvent, adding tert-butyllithium at the temperature of minus 75 ℃ to minus 80 ℃ for reaction for 1 hour, then adding 1, 2-dibromobenzene for reaction for 2 to 24 hours to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate;
Dissolving the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate in a solvent, adding n-butyllithium at the temperature of-75 to-80 ℃, stirring for 20-30 minutes, then adding disubstituted phosphine chloride, and reacting for 12-24 hours at room temperature to obtain a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton; or dissolving the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate in a solvent, adding tert-butyllithium at the temperature of minus 75 to minus 80 ℃, stirring for 1 hour, then adding copper chloride, reacting for 15 minutes, then adding disubstituted phosphine chloride, reacting at room temperature until the color of the mixture changes after the reaction, and then reacting at 140 ℃ for 16 to 24 hours to obtain the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton.
5. The method for producing a phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton according to claim 3 or 4, wherein in the step of producing the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, the molar ratio of 1-alkylpyrazole, n-butyllithium and 1, 2-dibromobenzene is 1.0:1.0 to 1.02:1.0 to 1.02 or the molar ratio of 1-alkylpyrazole, t-butyllithium and 1, 2-dibromobenzene is 1.0:1.0.
6. The method for producing a phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton according to claim 3 or 4, wherein in the step of producing a phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton, the molar ratio of 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, n-butyllithium and disubstituted chlorophosphine is 1.0:1.1:1.1 to 1.2 or the molar ratio of 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, t-butyllithium, copper chloride and disubstituted chlorophosphine is 1.0:2.0:1.0:1.2.
7. Use of a phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone as claimed in any of claims 1 to 2 as a synergist for transition metal catalysts in cross-coupling reactions;
The cross-coupling reaction is Xiong Tian coupling reaction or root bank coupling reaction.
8. The use according to claim 7, characterized in that the phosphine ligand of the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone is such that the molar amount of transition metal catalyst in the Xiong Tian coupling reaction system of enol pivalate is 0.5-4.0%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110175011.3A CN114907404B (en) | 2021-02-09 | 2021-02-09 | 5- (2- (Disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazolyl phosphine ligand and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110175011.3A CN114907404B (en) | 2021-02-09 | 2021-02-09 | 5- (2- (Disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazolyl phosphine ligand and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114907404A CN114907404A (en) | 2022-08-16 |
| CN114907404B true CN114907404B (en) | 2024-05-14 |
Family
ID=82761967
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110175011.3A Active CN114907404B (en) | 2021-02-09 | 2021-02-09 | 5- (2- (Disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazolyl phosphine ligand and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114907404B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115703806B (en) * | 2021-08-06 | 2024-05-14 | 香港理工大学深圳研究院 | Phosphine ligand of pyrazole-amide framework, and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107445989A (en) * | 2016-06-01 | 2017-12-08 | 香港理工大学深圳研究院 | A kind of Phosphine ligands of indoles skeleton and its preparation method and application |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102004052725B4 (en) * | 2004-10-27 | 2007-07-12 | Technische Universität Chemnitz | Process for the preparation of substituted phosphines and substituted phosphanes prepared by the process |
-
2021
- 2021-02-09 CN CN202110175011.3A patent/CN114907404B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107445989A (en) * | 2016-06-01 | 2017-12-08 | 香港理工大学深圳研究院 | A kind of Phosphine ligands of indoles skeleton and its preparation method and application |
Non-Patent Citations (2)
| Title |
|---|
| Bimetallic Cu/Pd Catalysts with Bridging Aminopyrimidinyl Phosphines for Decarboxylative Cross-Coupling Reactions at Moderate Temperature;Hackenberger, Dagmar et al;《ChemCatChem》;第7卷;3579-3588 * |
| Palladium-Phenylpyrazolylphosphine-Catalyzed Cross-Coupling of Alkenyl Pivalates;Zicong Chen et al;《Asian J. Org. Chem. 》;第10卷;776 – 779 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114907404A (en) | 2022-08-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110724164B (en) | Preparation method and application of 3-substituted chiral spiro aminophosphine ligand on pyridine ring | |
| CN109970795B (en) | Preparation method and application of 4-substituted chiral spiro aminophosphine ligand on pyridine ring | |
| CN111961087B (en) | Semi-sandwich ruthenium complex containing ortho-position carborane-based benzothiazole, and preparation and application thereof | |
| CN114907404B (en) | 5- (2- (Disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazolyl phosphine ligand and preparation method and application thereof | |
| CN109809967B (en) | Method for synthesizing chiral alcohol | |
| US9512155B2 (en) | Chiral phosphines for palladium-catalyzed asymmetric α-arylation of ester enolates to produce tertiary stereocenters in high enantioselectivity | |
| CN103748065B (en) | The manufacture method of 2-alkenyl amine compound | |
| CN104945434A (en) | (2-disubstituted phosphino-phenyl)-1-alkyl-indol-phosphine ligand and synthetic method and application thereof | |
| CN112175006A (en) | Preparation method of pyridine diphenylphosphine derivative | |
| CN107445989B (en) | Phosphine ligand with indole skeleton and preparation method and application thereof | |
| CN107459533B (en) | Benzimidazole-indole skeleton phosphine ligand and preparation method and application thereof | |
| CN110627831A (en) | Bibiaryl acetal phosphines, their preparation and use in coupling reactions | |
| CN106588983B (en) | Carbazolyl phosphorus ligand, preparation method and application thereof | |
| CN115703806B (en) | Phosphine ligand of pyrazole-amide framework, and preparation method and application thereof | |
| CN114805436B (en) | Organic phosphine oxide compound and synthesis method thereof | |
| CN108727179A (en) | A kind of alpha, beta-unsaturated ketone of α-allyl substitution, the synthetic method of ester or nitrile compound | |
| CN115260103B (en) | Preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole | |
| CN113856764B (en) | Transition metal catalyst and preparation method and application thereof | |
| US9340519B2 (en) | Paracyclophane-based ligands, their preparation and use in catalysis | |
| KR100915095B1 (en) | β- boration of α, β-alkyne ester compound | |
| CN109790079B (en) | C (sp) of organozinc reagents and heterocyclic (pseudo) halides3)-C(sp2) Cross-coupling reaction | |
| WO2024026596A1 (en) | METHOD FOR SYNTHESIZING α-LINEAR ALKYL SUBSTITUTED HETEROARENE | |
| CN106966877B (en) | 1, 4-dicarbonyl compound and preparation method thereof | |
| CN117715882A (en) | Method | |
| WO2016056669A1 (en) | Solid-supported ruthenium-diamine complex, and method for manufacturing optically active compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |