CN114907404A - 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazolylphosphine ligand and preparation method and application thereof - Google Patents
5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazolylphosphine ligand and preparation method and application thereof Download PDFInfo
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- CN114907404A CN114907404A CN202110175011.3A CN202110175011A CN114907404A CN 114907404 A CN114907404 A CN 114907404A CN 202110175011 A CN202110175011 A CN 202110175011A CN 114907404 A CN114907404 A CN 114907404A
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- Prior art keywords
- alkyl
- pyrazole
- phenyl
- disubstituted
- butyl
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- -1 2- (disubstituted phosphino) phenyl Chemical group 0.000 title claims abstract description 129
- 239000003446 ligand Substances 0.000 title claims abstract description 95
- 238000002360 preparation method Methods 0.000 title abstract description 12
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 160
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 81
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 35
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 25
- 150000003624 transition metals Chemical class 0.000 claims abstract description 25
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 24
- 125000003118 aryl group Chemical group 0.000 claims abstract description 24
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 18
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 17
- 239000011737 fluorine Substances 0.000 claims abstract description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 54
- 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 27
- 238000006880 cross-coupling reaction Methods 0.000 claims description 26
- 239000003054 catalyst Substances 0.000 claims description 21
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 claims description 20
- 238000005859 coupling reaction Methods 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
- 238000003756 stirring Methods 0.000 claims description 17
- 208000025174 PANDAS Diseases 0.000 claims description 14
- 208000021155 Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection Diseases 0.000 claims description 14
- 240000004718 Panda Species 0.000 claims description 14
- 235000016496 Panda oleosa Nutrition 0.000 claims description 14
- 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- REJGOFYVRVIODZ-UHFFFAOYSA-N phosphanium;chloride Chemical class P.Cl REJGOFYVRVIODZ-UHFFFAOYSA-N 0.000 claims description 10
- 229950010765 pivalate Drugs 0.000 claims description 10
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000002496 methyl group Chemical group [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
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- USJRLGNYCQWLPF-UHFFFAOYSA-N chlorophosphane Chemical class ClP USJRLGNYCQWLPF-UHFFFAOYSA-N 0.000 claims description 6
- 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
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 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
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- 239000004593 Epoxy Substances 0.000 claims description 2
- 241000274177 Juniperus sabina Species 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 238000007333 cyanation reaction Methods 0.000 claims description 2
- 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
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000000466 oxiranyl group Chemical group 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 60
- 229910052763 palladium Inorganic materials 0.000 abstract description 30
- 230000003197 catalytic effect Effects 0.000 abstract description 23
- 238000006555 catalytic reaction Methods 0.000 abstract description 5
- 125000001153 fluoro group Chemical group F* 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 56
- 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
- 239000000543 intermediate Substances 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000000843 powder Substances 0.000 description 10
- 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
- 239000011248 coating agent Substances 0.000 description 7
- 238000000576 coating method Methods 0.000 description 7
- 239000004809 Teflon Substances 0.000 description 6
- 229920006362 Teflon® Polymers 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- 238000010926 purge Methods 0.000 description 5
- 238000000926 separation method Methods 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
- 239000000758 substrate Substances 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
- 238000006411 Negishi coupling reaction Methods 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 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
- 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
- 230000007704 transition Effects 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
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 150000005347 biaryls Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 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
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 239000003814 drug Substances 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
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 238000010651 palladium-catalyzed cross coupling reaction Methods 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
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 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
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 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
- 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
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012450 pharmaceutical intermediate 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
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 description 1
- 229940096998 ursolic acid Drugs 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
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- 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 as the following formula I:
wherein, R is 1 Is alkyl or aryl, said R 2 Is alkyl or aryl, said R 3 Is hydrogen, alkylAlkoxy, aryl or fluoro, said R 4 Is alkyl or aryl, said R 5 Is hydrogen, alkyl, alkoxy, aryl or fluorine, said R 6 Is hydrogen, alkyl, alkoxy, aryl or fluorine. The phosphine ligand with the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework can form a complex with a stable structure with transition metal such as palladium, 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.
Description
Technical Field
The invention relates to the technical field of organic compounds and synthesis, in particular to a phosphine ligand with a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole 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. In the field of forming carbon-carbon bonds, cross-coupling reactions of Suzuki (Suzuki), Hiyama (Hiyama), radicular (Negishi), panda (Kumada), Stille (Stille), and the like are common methods for preparing alkenyl, biaryl, and/or related compounds. Olefins constitute an important structure in valuable natural products, pharmaceuticals, materials and bioactive agents. Alkenyl halides are a common 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, carboxylic esters, and carbamates, are readily synthesized from the corresponding carbonyl compounds and contain a wide variety of substituents.
Ligands play a considerable role in transition metal-catalyzed cross-coupling reactions. In particular, the ligand can effectively regulate the performance of the catalyst, and the coupling reaction is more perfectly developed. At present, the commonly used ligand is generally an organic phosphine compound, and the researches on phosphine ligands for many years show that the slight changes of the position, the size, the steric hindrance, the electrical property and the like of a substituent group on a phosphine ligand framework can generate important influence on the result of the coupling reaction. Among the well-known phosphine ligands, for example: phosphine ligands from the Fu, Beller, Buchwald, and 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 electric property of the ligand can be adjusted by changing substituent groups on pyrazole and benzene rings; in addition, the coordination performance of the ligand can be changed by changing the substituent group on the phosphorus atom.
Although many types of phosphine ligands have been widely used in coupling reactions, no single or single series of phosphine ligands have been able to solve all the problems of cross-coupling reactions to date. The key to solving the problem of coupling and bonding lies in searching a proper catalytic system, especially searching an effective ligand. In the coupling reaction of enol ester electrophiles such as enol carboxylate, particularly enol carboxylate with low activity is a substrate with high difficulty and high catalytic activity, so that the reaction has still great challenges so far. Therefore, designing phosphine ligands with high catalytic activity, stable structure and simple synthesis has a great influence in the reaction.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton, 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 easiness in preparation, stable structure and poor catalytic activity when being used as a synergist of a transition metal catalyst.
The technical scheme of the invention is as follows:
in a first aspect of the present invention, there is provided a phosphine ligand having a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone, which has the following structural formula i:
wherein, R is 1 Is alkyl or aryl, said R 2 Is alkyl or aryl, said R 3 Is hydrogen, alkyl, alkoxy, aryl or fluorine, said R 4 Is alkyl or aryl, said R 5 Is hydrogen, alkyl, alkoxy, aryl or fluorine, said R 6 Is hydrogen, alkyl, alkoxy, aryl or fluorine.
In a second aspect of the present invention, there is provided a method for preparing a phosphine ligand having a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone, comprising the steps of:
reacting 1-alkyl pyrazole, n-butyl lithium and 1, 2-dibromobenzene to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate; or reacting 1-alkyl pyrazole, tert-butyl lithium 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 with a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton; or reacting the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, tert-butyl lithium, copper chloride and disubstituted phosphine chloride to obtain the phosphine ligand with a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton.
In a third aspect, the invention provides the use of a phosphine ligand with a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework as a synergist for a transition metal catalyst in a cross-coupling reaction.
Has the advantages that: the phosphine ligand with the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework can form a complex with a stable structure with transition metal such as palladium, 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 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton and transition metal such as palladium can be used for preparing various synthetic products such as biaryl compounds and polysubstituted alkenyl compounds, and has great application potential in the synthesis of natural products and drug intermediates. The phosphine ligand with the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework provided by the invention can be widely used for high-difficulty transition metal-catalyzed cross coupling reactions, including a panda coupling Reaction (Kumada Reaction) and a root-bank coupling Reaction (Negishi Reaction) of enol pivalate. The catalytic activity of the transition metal catalyst such as palladium catalyst can be as low as 0.5 mol%, the separation yield is as high as 95%, and the method has profound significance in cross-coupling reaction; and simultaneously compatible with functional groups such as ester, ketone, methoxyl and the like. In addition, the phosphine ligand with the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton has stability to air and moisture and is easy to store; and the spatial structure and the electric property of the ligand can be adjusted 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 with 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 with the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework provided by the invention can be widely used as a synergist of a transition metal catalyst, is used for a cross-coupling reaction, and forms a complex with a stable structure with a transition metal such as palladium, so that the catalytic activity of the transition metal such as palladium during a catalytic reaction is improved, and particularly, the phosphine ligand can be suitable for a panda coupling reaction and a root-bank coupling reaction of high-difficulty neopentanoic acid enol ester, the catalytic activity of the transition metal catalyst such as a palladium catalyst can be as low as 0.5 mol%, and the separation yield is as high as 95%.
Detailed Description
The present invention provides a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton, a preparation method and an application thereof, and the present invention is further described in detail below in order to make the objects, technical schemes and effects of the present invention clearer and clearer. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
The embodiment of the invention provides a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton, which has the following structure shown as the following formula I:
wherein, R is 1 Is alkyl or aryl, said R 2 Is alkyl or aryl, R 3 Is hydrogen, alkyl, alkoxy, aryl or fluorine, said R 4 Is alkyl or aryl, said R 5 Is hydrogen, alkyl, alkoxy, aryl or fluorine, said R 6 Is hydrogen, alkyl, alkoxy, aryl or fluorine.
In the above formula I, it is particularly preferred that R is 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; said R is 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-bis (trifluoromethyl) phenyl and 1-naphthyl; the R is 3 Is one of hydrogen, alkyl of C1-10, alkoxy of C1-C10, phenyl, fluorine and trifluoromethyl; the R is 4 Is one of C1-C10 alkyl, C3-10 cycloalkyl, oxygen heterocycle, epoxy alkyl, alkoxy alkyl, oxygen heterocycle and phenyl; said R is 5 Is one of hydrogen, alkyl of C1-10, alkoxy of C1-C10, phenyl, fluorine and trifluoromethyl; said R is 6 Is one of hydrogen, C1-10 alkyl, C1-C10 alkoxy, phenyl, fluorine and trifluoromethyl.
Further, said R 3 The alkyl group of C1-C10 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and alkyl groups of C5-C10, and the alkoxy group of C1-C10 includes methoxy, ethoxy, n-propoxy, isopropoxy and alkoxy groups of C4-C10;
said R is 4 Wherein the C1-C10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C5-C10 alkyl, the C3-10 cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and C7-C10 cycloalkyl groups, the oxa ring includes tetrahydrofuran, the epoxyalkyl group includes epoxypropyl, the alkoxyalkyl group includes methoxymethyl, and the oxa cycloalkyl group includes tetrahydrofuryl;
the R is 5 The C1-C10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butylAlkyl of C5-10, the alkoxy of C1-C10 includes methoxy, ethoxy, n-propoxy, isopropoxy and alkoxy of C4-C10;
the R is 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 above preferred 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton can be combined with a transition metal such as palladium to obtain a catalytic system with better catalytic effect, and various synthetic products such as multi-substituted olefin compounds can be prepared.
The phosphine ligand with the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole framework provided by the embodiment of the invention can form a complex with a stable structure with transition metal such as palladium, 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 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton and transition metal such as palladium can be used for preparing 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 with the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton provided by the embodiment of the invention can be suitable for high-difficulty transition metal-catalyzed cross-coupling reactions such as a panda cross-coupling Reaction (Kumada Reaction) and a root-shore cross-coupling Reaction (Negishi Reaction) of enol pivalate. The catalytic activity of a transition metal catalyst such as a palladium catalyst can be as low as 0.5 mol%, the separation yield is as high as 95%, and the method has profound significance in cross-coupling reaction; and simultaneously compatible with functional groups such as ester, ketone, methoxyl and the like. In addition, the phosphine ligand with the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton disclosed in the embodiment of the invention has stability to air and moisture and is easy to store; and the spatial structure and the electric property of the ligand can be adjusted 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 with a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton, which comprises the following steps:
reacting 1-alkyl pyrazole, n-butyl lithium and 1, 2-dibromobenzene to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate; or reacting 1-alkyl pyrazole, tert-butyl lithium 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 with a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton; or reacting the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, tert-butyl lithium, copper chloride and disubstituted phosphine chloride to obtain the phosphine ligand with a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton.
As a specific example, the preparation method of the phosphine ligand with 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton comprises the following steps:
s01, dissolving 1-alkyl pyrazole in a solvent (such as tetrahydrofuran), adding n-butyl lithium at 0 ℃, uniformly stirring for 2 hours, then adding 1, 2-dibromobenzene, and reacting at room temperature for 2-24 hours to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate; or dissolving 1-alkyl pyrazole in tetrahydrofuran, adding tert-butyl lithium at-75 to-80 deg.c, preferably-78 deg.c, and reacting at room temperature for 1 hr. Then adding 1, 2-dibromobenzene at the temperature of 0 ℃, and reacting 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 ℃, more preferably at a temperature of-78 ℃, 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 the intermediate 5- (2-bromophenyl) -1-alkyl-1H-pyrazole in toluene, adding tert-butyl lithium at-75- -80 deg.c, preferably-78 deg.c, and stirring for 1 hr. Copper chloride was then added and the reaction was allowed to proceed for 15 minutes. Then, disubstituted phosphine chloride was added thereto and reacted at room temperature until the color of the mixture was changed after the reaction. Then reacting for 16-24 hours at 140 ℃ to obtain the phosphine ligand with 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton.
Specifically, in step S01, the reaction scheme for preparing the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate is as follows:
in order to obtain better reaction effect, the molar ratio of the 1-alkyl pyrazole, the n-butyl lithium and the 1, 2-dibromo benzene is preferably 1.0 (1.0-1.02) to 1.0-1.02. More preferably, the 1-alkyl pyrazole is dissolved in tetrahydrofuran, n-butyl lithium is added at the temperature of 0 ℃ and the proportion of 1.0 (1.0-1.02), and the mixture is uniformly stirred for 2 hours; then 1, 2-dibromobenzene was added in a ratio of 1.0 (1.0 to 1.02) and reacted at room temperature for 2 hours.
Preferably, after the thin-layer chromatography detects that the substrate is completely consumed, adding water to stop the reaction, adding ethyl acetate to extract and separate; 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 noteworthy that the molar ratio of the 1-alkyl pyrazole, the tert-butyl lithium and the 1, 2-dibromobenzene can also be 1.0:1.0:1.0 for the preparation of the examples of the present invention. More preferably, the 1-alkyl pyrazole is dissolved in tetrahydrofuran, under the condition of-75 to-80 ℃, more preferably-78 ℃, tert-butyl lithium is added in the proportion of 1.0:1.0, and the reaction is carried out for 2 hours at room temperature; 1, 2-dibromobenzene is then added in a ratio of 1.0:1.0 and reacted at room temperature for 2 to 24 hours.
Further preferably, after the thin layer chromatography detection substrate is completely consumed, water is added to stop the reaction, and ethyl acetate is added to extract and separate; 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, which has the formula:
in the above step S02, as a preferable example, in the step of preparing the phosphine ligand of 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). More preferably, the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate is dissolved in tetrahydrofuran, n-butyllithium is added at a ratio of 1.0:1.1 at a temperature of-75 to-80 ℃, more preferably-78 ℃, and the mixture is uniformly stirred for 20 to 30 minutes; then adding disubstituted chlorophosphine in the proportion of 1.0 (1.1-1.2), and stirring for reaction at room temperature for 12-24 hours. The reaction formula of the above S02 is as follows:
further preferably, after the completion of the reaction, all the solvent is removed under reduced pressure, and the reaction mixture is washed three times with cold methanol to obtain a powdered phosphine ligand having a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton.
It is noteworthy that the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, tert-butyllithium, copper chloride and disubstituted chlorophosphine can also be prepared in a molar ratio of 1.0:2.0:1.0: 1.2. Dissolving the intermediate 5- (2-bromophenyl) -1-alkyl-1H-pyrazole in toluene, adding tert-butyllithium in a ratio of 1.0:2.0 at-75-80 deg.C, preferably-78 deg.C, and stirring for 1 hr; copper chloride was then added in a ratio of 1.0:1.0 and reacted for 15 minutes. The disubstituted phosphonium chloride was then added in a ratio of 1.0:1.2 and reacted at room temperature until the color of the mixture changed. Then reacted at 140 ℃ for 16 to 24 hours to obtain a phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton, which has the following reaction formula:
further preferably, after the thin layer chromatography detects that the substrate is completely consumed, adding ethyl acetate, adding 30% ammonia water for extraction, separating and repeatedly extracting until the color of an organic phase is colorless; the organic phase is concentrated after drying over sodium sulfate and purified by column chromatography to obtain the powdered phosphine ligand with 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton.
The preparation method of the phosphine ligand with 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 with 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, a panda coupling reaction, a root-and-shore coupling reaction, a suzuki coupling reaction, a sabina coupling reaction, a boron-based coupling reaction, and a cyanation reaction.
Preferably, the transition metal catalyst is a palladium catalyst.
The phosphine ligand with 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, is used for a cross-coupling reaction, and forms a complex with a stable structure with a transition metal such as palladium, so that the catalytic activity of the transition metal such as palladium during a catalytic reaction is improved, and particularly, the phosphine ligand can be suitable for difficult coupling reactions of a panda and a root bank of neopentanoate, the catalytic activity of the transition metal catalyst such as a palladium catalyst can be as low as 0.5 mol%, and the separation yield can be as high as 95%.
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-mouth bottle, 0.886 g of 1-Methylpyrazole (10.8 mmol). After 3 times of nitrogen exchange, 30 ml of freshly distilled tetrahydrofuran were added with nitrogen and stirred uniformly. After the mixture was cooled to 0 ℃ and n-butyllithium (11.0mmol) was added dropwise, the reaction was carried out for 2 hours. 1.3 ml of 1, 2-dibromobenzene (11.0mmol) are then added dropwise. The reaction was left at room temperature for 2 hours. Then, 20ml of water was added to the system, 100 ml of ethyl acetate was added thereto three times to extract, 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 the intermediate 5- (2-bromophenyl) -1-methyl-1H-pyrazole as a yellow powder in 29% yield. 1 H NMR(400MHz,CDCl 3 )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 (3.825mmol) was weighed in. After 3 times of nitrogen exchange, 40 ml of freshly distilled tetrahydrofuran were added with nitrogen and stirred uniformly. After the mixture was cooled to-78 deg.C, n-butyllithium (4.2mmol) was added dropwise, and the reaction was carried out for 20 minutes. Then 1.0 ml of dicyclohexylphosphonium chloride (4.59mmol) was added dropwise. The reaction was allowed to stand at room temperature for 20 hours. After all the solution was pumped out under reduced pressure, it was washed three times with cold methanol to give 0.51 g of pure 5- (2- (dicyclohexylphosphino) phenyl) -1-methyl-1H-pyrazole as a white powder in 37% yield. 1 H NMR(400MHz,CDCl 3 )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 (2.90mmol) was weighed in. After 3 times of nitrogen exchange, 40 ml of freshly distilled tetrahydrofuran was added with nitrogen and stirred uniformly. After the mixture was cooled to-78 deg.C, n-butyllithium (3.2mmol) was added dropwise, and the reaction was carried out for 20 minutes. Then 0.55 ml of diisopropylphosphine chloride (3.50mmol) was added dropwise. The reaction was left at room temperature for 24 hours. All ofAfter the solution was removed under reduced pressure and washed three times with cold methanol, the pure product 5- (2- (diisopropylphosphino) phenyl) -1-methyl-1H-pyrazole was obtained as a white powder in 0.60 g with a yield of 75%. 1 H NMR(400MHz,CDCl 3 )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 100 ml two-necked flask, 2.4 g of 1-ethylpyrazole (25.0mmol) were weighed in. After 3 times of nitrogen exchange, 40 ml of freshly distilled tetrahydrofuran was added with nitrogen and stirred uniformly. After the mixture was cooled to 0 ℃ and n-butyllithium (25.0mmol) was added dropwise, the reaction was carried out for 2 hours. Then 3.0 ml of 1, 2-dibromobenzene (25.0mmol) were added dropwise. The reaction was allowed to stand at room temperature for 2 hours. Then, 20ml of water was added to the system, 100 ml of ethyl acetate was added thereto three times to extract, 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 the intermediate 5- (2-bromophenyl) -1-ethyl-1H-pyrazole as an orange liquid product in 30% yield. 1 H NMR(400MHz,CDCl 3 )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 100 ml two-necked flask, 0.753 g of 5- (2-bromophenyl) -1-ethyl-1H-pyrazole (3.0mmol) was weighed in. After 3 times of nitrogen exchange, 30 ml of freshly distilled tetrahydrofuran were added with nitrogen and stirred uniformly. After the mixture was cooled to-78 deg.C, n-butyllithium (3.3mmol) was added dropwise, and the reaction was carried out for 20 minutes. Then, 0.73 ml of dicyclohexylphosphonium chloride (3.3mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 18-24 hours. After all the solution was pumped out under reduced pressure and washed three times with cold methanol, the pure product 5- (2- (dicyclohexylphosphino) phenyl) -1-ethyl-1H-pyrazole was obtained as a white powder in 0.17 g with a yield of 16%. 1 H NMR(400MHz,CDCl 3 )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 (30.0mmol) was weighed in. After 3 times of nitrogen exchange, 40 ml of freshly distilled tetrahydrofuran were added with nitrogen and stirred uniformly. After the mixture was cooled to-78 deg.C, t-butyllithium (30.0mmol) was added dropwise, and the reaction was carried out at room temperature for 1 hour. The mixture was then cooled to 0 ℃ and then 3.6 ml of 1, 2-dibromobenzene (29.7mmol) were added dropwise. The reaction was allowed to stand at room temperature for 2 hours. Then, 20ml of water was added to the system, 100 ml of ethyl acetate was added thereto three times to extract, and the organic phases were combined and dried over anhydrous sodium sulfate. After removing all the solution under reduced pressure, the concentrated reaction mixture was purified by column chromatography to give 2.72 g of the intermediate 5- (2-bromophenyl) -1-isopropyl-1H-pyrazole as a yellow powder in 34% yield. 1 H NMR(400MHz,CDCl 3 )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 (3.0mmol) was weighed in. After 3 times of nitrogen exchange, 30 ml of freshly distilled tetrahydrofuran was added with nitrogen and stirred uniformly. After the mixture was cooled to-78 deg.C, n-butyllithium (3.3mmol) was added dropwise, and the reaction was carried out for 20 minutes. Then, 0.73 ml of dicyclohexylphosphonium chloride (3.3mmol) was added dropwise. The reaction was allowed to stand at room temperature for 18 hours. After all the solution was pumped out under reduced pressure, it was washed three times with cold methanol to give 0.57 g of pure 5- (2- (dicyclohexylphosphino) phenyl) -1-isopropyl-1H-pyrazole as a white powder in 50% yield. 1 H NMR(400MHz,CDCl 3 )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 100 ml two-necked flask, 0.795 g of 5- (2-bromophenyl) -1-isopropyl-1H-pyrazole (3.0mmol) was weighed in. After 3 times of nitrogen exchange, 30 ml of freshly distilled tetrahydrofuran were added with nitrogen and stirred uniformly. After the mixture was cooled to-78 deg.C, n-butyllithium (3.3mmol) was added dropwise, and the reaction was carried out for 20 minutes. Then 0.53 ml of diisopropylphosphine chloride (3.3mmol) was added dropwise. The reaction was left at room temperature for 18 hours. After all the solution was pumped under reduced pressure and washed three times with cold methanol, the pure product 5- (2- (diisopropylphosphino) phenyl) -1-isopropyl-1H-pyrazole was obtained as a pale yellow powder in 0.72 g with a yield of 80%. 1 H NMR(400MHz,CDCl 3 )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-t-butylphosphino) phenyl) -1-isopropyl-1H-pyrazole
In a 50 ml Schlenk tube, 0.665 g of 5- (2-bromophenyl) -1-isopropyl-1H-pyrazole (2.5mmol) were weighed in. After the nitrogen gas was purged 3 times, 20ml of freshly distilled toluene was added under nitrogen gas introduction, and the mixture was stirred uniformly. After the mixture was cooled to-78 deg.C, t-butyllithium (5.0mmol) was added dropwise, and the reaction was carried out for 1 hour. Then, 0.248 g of copper chloride (2.5mmol) was added thereto, and the reaction was carried out for 15 minutes. Then 0.57 ml of di-tert-butylphosphine chloride (3.0mmol) were added dropwise. The reaction was left to stir at room temperature until the color of the mixture changed. The Schlenk tube was then placed in a preheated 140 ℃ oil bath for 16 hours. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction was stopped, ethyl acetate (50.0mL) was added to the system, and 50 mL of 30% aqueous ammonia was further added thereto in several portions for extraction until the color of the organic phase became colorless, and the organic phases were combined and dried over anhydrous sodium sulfate. After removing all the solution under reduced pressure, the concentrated reaction mixture was purified by column chromatography to give 0.53 g of pure 5- (2- (di-t-butylphosphino) phenyl) -1-isopropyl-1H-pyrazole as a white powder in 65% yield. 1 H NMR(400MHz,CDCl 3 )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 100 ml two-necked flask, 1.44 g of 1-phenylpyrazole (10.0mmol) were weighed in. After 3 times of nitrogen exchange, 40 ml of freshly distilled tetrahydrofuran were added with nitrogen and stirred uniformly. After the mixture was cooled to-78 deg.C, t-butyllithium (10.0mmol) was added dropwise and reacted at room temperature for 1 hour. The mixture was then cooled to 0 ℃ and 1.2 ml of 1, 2-dibromobenzene (10.0mmol) were added dropwise. The reaction was left at room temperature for 2 hours. Then, 20ml of water was added to the system, 100 ml of ethyl acetate was added thereto three times to extract, and the organic phases were combined and dried over anhydrous sodium sulfate. After removing all the solution under reduced pressure, the concentrated reaction mixture was purified by column chromatography to give 0.69 g of an intermediate 5- (2-bromophenyl) -1-phenyl-1H-pyrazole as a yellow powder in 23% yield. 1 H NMR(400MHz,CDCl 3 )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 (1.167mmol) was weighed in. After 3 times of nitrogen exchange, 20ml of freshly distilled tetrahydrofuran was added with nitrogen and stirred uniformly. After the mixture was cooled to-78 deg.C, n-butyllithium (1.3mmol) was added dropwise, and the reaction was carried out for 20 minutes. Then, 0.29 ml of dicyclohexylphosphonium chloride (1.3mmol) was added dropwise. The reaction was allowed to stand at room temperature for 18 hours. After all the solution was pumped under reduced pressure and washed three times with cold methanol, the pure product 5- (2- (dicyclohexylphosphino) phenyl) -1-phenyl-1H-pyrazole was obtained as a yellow powder in 0.27 g with a yield of 56%. 1 H NMR(400MHz,CDCl 3 )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)。
Further, 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazoles shown in Table 1 below can be prepared by a method described by referring to the following reaction formula.
TABLE 1
Example 8: application of phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton in palladium-catalyzed panda (Kumada) cross-coupling Reaction and root-bank cross-coupling Reaction (Negishi Reaction) of neopentanoate enol ester.
8.1 inventive example 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone of the phosphine ligand several catalysts, the structure of which is shown below as cat1-7, catalyze the panda (Kumada) cross-coupling reaction:
there was added triethylamine by placing palladium acetate (0.0018 g, 0.008mmol) and a magnetic stir bar fitted with a teflon coating into a 20mL Schlenk tube, replacing the system with nitrogen blanket, then adding 0.8mL of freshly distilled tetrahydrofuran and stirring them uniformly for 1 minute. At the same time, a phosphine ligand (palladium: phosphine ligand ratio 2.0 mol%: 2 mol%) and a magnetic stir bar equipped with a polytetrafluoroethylene coating were placed into another 20mL Schlenk tube. After 3 nitrogen purges, the corresponding amounts (e.g., 0.4mL, 2.0 mol%) and triethylamine (0.05mL) were purged from the stock palladium solution using a gas-tight syringe into a Schlenk tube loaded with phosphine ligand and protected with nitrogen. The solution of palladium complex was heated for about 1 to 2 minutes until the solvent started to boil, and stirred at room temperature for 5 minutes. 3, 4-dihydronaphthalen-2-yl pivalate (0.2mmol) and Grignard reagent in tetrahydrofuran (0.4mmol) were then added under nitrogen. The Schlenk tube was then left to react at room temperature for 10 minutes. Ethyl acetate (4.0mL) and water (2.0mL) were then added to the system, and the extracted organic layer was analyzed by gas chromatography and checked to determine the yield of the coupled product.
Procedure without addition of triethylamine palladium acetate (0.0018 g, 0.008mmol), phosphine ligand (palladium: phosphine ligand ratio 4.0 mol%: 4 mol%) and a magnetic stir bar equipped with a teflon coating were placed in a 20mL Schlenk tube, the system was replaced with nitrogen blanket, then 0.8mL of freshly distilled tetrahydrofuran was added and they were stirred uniformly for 1 minute to form palladium complex. At the same time, a magnetic stir bar equipped with a teflon coating was placed into another 20mL Schlenk tube. After 3 nitrogen purges, the corresponding amount (e.g., 0.4mL, 2.0 mol%) was purged from the stock palladium complex solution into a Schlenk tube protected with nitrogen using a gas-tight syringe. The solution of palladium complex was heated for about 1 to 2 minutes until the solvent started to boil, and stirred at room temperature for 5 minutes. 3, 4-dihydronaphthalen-2-yl pivalate (0.2mmol) and Grignard reagent in tetrahydrofuran (0.4mmol) were then added under nitrogen. The Schlenk tube was then left to react at room temperature for 10 minutes. Ethyl acetate (4.0mL) and water (2.0mL) were then added to the system, and the extracted organic layer was subjected to gas chromatography and checked to determine the yield of the coupled product.
Wherein, in the catalytic panda cross-coupling reaction, the conditions of the catalyst phosphine ligand and the yield are shown in the following table 2.
TABLE 2
As can be seen from Table 2, each of the above phosphine ligands having a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton exhibited excellent catalytic performance in the above-mentioned panda coupling reaction, and had better catalytic efficiency than other commercially available ligands.
8.2, 5- (2- (dicyclohexylphosphino) phenyl) -1-isopropyl-1H-pyrazole catalyzed panda cross-coupling reaction of enol pivalate
Palladium acetate (0.0018 g, 0.008mmol), phosphine ligand (palladium: phosphine ligand ratio 4.0 mol%: 4-16 mol%), and enol pivalate (0.2mmol if solid) and a magnetic stir bar fitted with a teflon coating were placed in a 20mL Schlenk tube. After purging nitrogen 3 times, the enol pivalate (0.2mmol if liquid) was added while passing nitrogen, and tetrahydrofuran (0.4mL) and Grignard reagent (0.4mmol) in tetrahydrofuran were freshly distilled. The Schlenk tube was then placed in an oil bath at room temperature or preheated to 50 ℃ or 110 ℃ for 1-24 hours, the reaction scheme is shown below. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction was stopped, ethyl acetate (4.0mL) and water (2.0mL) were added to the system, and then the extracted organic layer was subjected to gas chromatography. After which about 10mL of ethyl acetate are added three to four times each for extraction and the organic phases are combined. The organic phase is concentrated under reduced pressure and purified by silica gel column chromatography to give the cross-coupled product.
Wherein, in the catalytic panda cross-coupling reaction, the dosage of palladium, the phosphine ligand of the catalyst and the yield are shown in the following table 3.
TABLE 3
8.3, 5- (2- (dicyclohexylphosphino) phenyl) -1-isopropyl-1H-pyrazole catalyzed root-bank cross-coupling reaction of enol pivalate
A magnetic stir bar with Teflon coating was placed in a 20mL Schlenk tube, the system replaced with nitrogen blanket, then zinc chloride (0.4mmol) in tetrahydrofuran was added and it was stirred at 0 deg.C for 1 minute. Then, grignard reagent (0.8mmol) was added in tetrahydrofuran as a solvent and stirred at room temperature for 30 minutes, thereby obtaining an organozinc reagent.
Palladium acetate (0.0018 g, 0.008mmol), phosphine ligand (palladium: phosphine ligand ratio 4.0 mol%: 4.0 mol%), and enol pivalate (0.2mmol, if solid) and a magnetic stir bar fitted with a Teflon coating were placed in another 20mL Schlenk tube. After 3 nitrogen purges, the enol pivalate (0.2mmol if liquid) was added with nitrogen purge, the tetrahydrofuran (0.4mL) and the freshly prepared organozinc reagent were freshly distilled. The Schlenk tube was then left to react at room temperature for 4-6 hours, and the reaction formula is shown below. After the completion of the reaction, the reaction tube was cooled to room temperature, the reaction was stopped, ethyl acetate (4.0mL) and water (2.0mL) were added to the system, and then the organic layer after extraction was subjected to gas chromatography. After which about 10mL of ethyl acetate are added three to four times each for extraction and the organic phases are combined. The organic phase is concentrated under reduced pressure and purified by silica gel column chromatography to give the cross-coupled product.
In the above catalytic radical-shore cross-coupling reaction, the amount of palladium, the phosphine ligand of the catalyst and the yield are shown in table 4 below.
TABLE 4
As can be seen from table 3 and table 4 above, when the phosphine ligand of 5- (2- (dicyclohexylphosphino) phenyl) -1-isopropyl-1H-pyrazole framework in the embodiment of the present invention is used for the first palladium-catalyzed cross-coupling reaction between the ursolic acid and the roots and the banks of the enol pivalate, the palladium usage (mol%) can be greatly reduced, and the separation yield can reach 95% between 0.5 and 4.0, even at room temperature.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
Claims (10)
1. A phosphine ligand with a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton is characterized in that the structural formula is shown as the following formula I:
wherein, R is 1 Is alkyl or aryl, said R 2 Is alkyl or aryl, said R 3 Is hydrogen, alkyl, alkoxy, aryl or fluorine, said R 4 Is alkyl or aryl, said R 5 Is hydrogen, alkyl, alkoxy, aryl or fluorine, said R 6 Is hydrogen, alkyl, alkoxy, aryl or fluorine.
2. The phosphine ligand with 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone according to claim 1, wherein R is 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-di (trifluoromethyl) phenyl and 1-naphthyl; the R is 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; said R is 3 Is hydrogen, C1-C10 alkyl, C1-C10 alkoxy, phenyl, fluorine, trifluoromethylOne of the groups; the R is 4 Is one of C1-C10 alkyl, C3-C10 cycloalkyl, oxygen heterocycle, epoxy alkyl, alkoxy alkyl, oxygen heterocycle alkyl and phenyl; the R is 5 Is one of hydrogen, alkyl of C1-C10, alkoxy of C1-C10, phenyl, fluorine and trifluoromethyl; the R is 6 Is one of hydrogen, C1-C10 alkyl, C1-C10 alkoxy, phenyl, fluorine and trifluoromethyl.
3. The phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton according to claim 2, wherein R is 3 The alkyl group of C1-C10 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and alkyl groups of C5-C10, and the alkoxy group of C1-C10 includes methoxy, ethoxy, n-propoxy, isopropoxy and alkoxy groups of C4-C10;
the R is 4 Wherein the C1-C10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C5-C10 alkyl, the C3-C10 cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and C7-C10 cycloalkyl, the oxirane ring includes tetrahydrofuran, the epoxyalkyl group includes epoxypropyl, the alkoxyalkyl group includes methoxymethyl, and the oxacycloalkyl group includes tetrahydrofuryl;
said R is 5 The C1-C10 alkyl group comprises methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-C10 alkyl, and the C1-C10 alkoxy group comprises methoxy, ethoxy, n-propoxy, isopropoxy and C4-C10 alkoxy;
the R is 6 The alkyl group of C1-C10 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and alkyl groups of C5-C10, and the alkoxy group of C1-C10 includes methoxy, ethoxy, n-propoxy, isopropoxy and alkoxy groups of C4-C10.
4. A method for preparing a phosphine ligand of a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton is characterized by comprising the following steps:
reacting 1-alkyl pyrazole, n-butyl lithium and 1, 2-dibromobenzene to obtain a 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate; or reacting 1-alkyl pyrazole, tert-butyl lithium 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 with a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton; or reacting the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, tert-butyl lithium, copper chloride and disubstituted phosphine chloride to obtain the phosphine ligand with a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton.
5. The method for producing a phosphine ligand having a 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton according to claim 4, which comprises the steps of:
dissolving 1-alkyl pyrazole in a solvent, adding n-butyl lithium at the temperature of 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-alkyl pyrazole in a solvent, adding tert-butyl lithium at the temperature of-75 to-80 ℃, reacting for 1 hour, then adding 1, 2-dibromobenzene, and reacting 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-butyl lithium at the temperature of-75 to-80 ℃, stirring for 20-30 minutes, then adding disubstituted phosphine chloride, and reacting at room temperature for 12-24 hours 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-butyl lithium at the temperature of-75 to-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 for 16 to 24 hours at the temperature of 140 ℃ to obtain the phosphine ligand with the 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton.
6. The method for producing a phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton according to claim 4 or 5, wherein in the step of producing the intermediate of 5- (2-bromophenyl) -1-alkyl-1H-pyrazole, the molar ratio of the 1-alkylpyrazole, n-butyllithium and 1, 2-dibromobenzene is 1.0:1.0 to 1.02 or the molar ratio of the 1-alkylpyrazole, t-butyllithium and 1, 2-dibromobenzene is 1.0:1.0: 1.0.
7. The method for producing a phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton according to claim 4 or 5, wherein the molar ratio of the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, n-butyllithium and disubstituted chlorophosphine in the step of producing the phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole intermediate, is 1.0:1.1:1.1-1.2 or the molar ratio of the 5- (2-bromophenyl) -1-alkyl-1H-pyrazole intermediate, t-butyllithium, copper chloride and disubstituted chlorophosphine is 1.0:2.0:1.0: 1.2.
8. Use of the phosphine ligands of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole backbone as claimed in any of claims 1 to 3 as synergists for transition metal catalysts in cross-coupling reactions.
9. Use according to claim 8, wherein the cross-coupling reaction comprises a panda coupling reaction, a root-and-shore coupling reaction, a suzuki coupling reaction, a sabina coupling reaction, a boron-based coupling reaction and a cyanation reaction.
10. The use according to claim 8, wherein the phosphine ligand of 5- (2- (disubstituted phosphino) phenyl) -1-alkyl-1H-pyrazole skeleton is used in an amount of 0.5 to 4.0% by mole in the panda coupling reaction system of enol pivalate.
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