CN105772094A - 一种手性氮杂环卡宾类催化剂及其应用 - Google Patents
一种手性氮杂环卡宾类催化剂及其应用 Download PDFInfo
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- CN105772094A CN105772094A CN201610250716.6A CN201610250716A CN105772094A CN 105772094 A CN105772094 A CN 105772094A CN 201610250716 A CN201610250716 A CN 201610250716A CN 105772094 A CN105772094 A CN 105772094A
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- Prior art keywords
- aryl
- chirality
- phenyl
- heterocyclic carbine
- alkyl
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- 239000003054 catalyst Substances 0.000 title claims abstract description 56
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 12
- 125000000623 heterocyclic group Chemical group 0.000 title abstract 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 title abstract 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 125000003118 aryl group Chemical group 0.000 claims abstract description 15
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 4
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 3
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 3
- 150000003624 transition metals Chemical group 0.000 claims abstract description 3
- -1 normal-butyl Chemical group 0.000 claims description 39
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- 230000000694 effects Effects 0.000 claims description 15
- 238000006555 catalytic reaction Methods 0.000 claims description 13
- 229910052763 palladium Inorganic materials 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 5
- 239000004327 boric acid Substances 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 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 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052804 chromium Inorganic materials 0.000 claims description 2
- 239000011651 chromium Substances 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- 125000004404 heteroalkyl group Chemical group 0.000 abstract 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- 239000000047 product Substances 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000000654 additive Substances 0.000 description 7
- 230000000996 additive effect Effects 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 229910000071 diazene Inorganic materials 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 4
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical group O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- CMIMBQIBIZZZHQ-UHFFFAOYSA-N 1-bromo-2-methylnaphthalene Chemical compound C1=CC=CC2=C(Br)C(C)=CC=C21 CMIMBQIBIZZZHQ-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000005347 biaryls Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
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- 239000007788 liquid Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- XNIGURFWNPLWJM-UHFFFAOYSA-N 1-bromo-2-methoxynaphthalene Chemical compound C1=CC=CC2=C(Br)C(OC)=CC=C21 XNIGURFWNPLWJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LEMABCWCFKCYQC-UHFFFAOYSA-N OBO.C1=CC=CC2=CC=CC=C21 Chemical class OBO.C1=CC=CC2=CC=CC=C21 LEMABCWCFKCYQC-UHFFFAOYSA-N 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000006074 cyclodimerization reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- GPNDARIEYHPYAY-UHFFFAOYSA-N palladium(ii) nitrate Chemical compound [Pd+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O GPNDARIEYHPYAY-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- INGIGRKEXZOVTB-SNVBAGLBSA-N (1s)-2,2-dimethyl-1-phenylpropan-1-amine Chemical compound CC(C)(C)[C@H](N)C1=CC=CC=C1 INGIGRKEXZOVTB-SNVBAGLBSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- QGRPVMLBTFGQDQ-UHFFFAOYSA-N 1-chloro-2-methoxybenzene Chemical compound COC1=CC=CC=C1Cl QGRPVMLBTFGQDQ-UHFFFAOYSA-N 0.000 description 1
- SVAZIMBLBHOVIR-UHFFFAOYSA-N 2-chloro-3-fluoropyridine Chemical compound FC1=CC=CN=C1Cl SVAZIMBLBHOVIR-UHFFFAOYSA-N 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
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- 235000009508 confectionery Nutrition 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
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- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 1
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- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
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- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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Classifications
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- 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
- B01J31/22—Organic complexes
- B01J31/2265—Carbenes or carbynes, i.e.(image)
- B01J31/2269—Heterocyclic carbenes
- B01J31/2273—Heterocyclic carbenes with only nitrogen as heteroatomic ring members, e.g. 1,3-diarylimidazoline-2-ylidenes
-
- 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
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/04—Substitution
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- 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
- C07C1/321—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 non-metal atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
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Abstract
本发明涉及一种手性氮杂环卡宾类催化剂及其应用，催化剂的化学结构式如下：上述分子结构中至少包含有两个手性碳原子，其中，R1、R2、R3、R4分别独立地代表H、烷基、杂烷基或芳基，R5、R6分别独立地代表H、卤素、烷基、杂烷基或芳基，X、Y分别独立地代表含碳原子基团或含杂原子基团，Z代表烷基、杂烷基或芳基，M为过渡金属；本发明催化剂用于催化不对称Suzuki交叉偶联反应。与现有技术相比，本发明手性氮杂环卡宾类催化剂至少包含两个手性碳原子，手性碳原子所连接基团充分可调，在Suzuki交叉偶联反应中表现出极高的催化活性以及立体选择性，是一类新型催化剂，具有很好的应用前景。
Description
技术领域
本发明属于有机化学合成技术领域，涉及一种手性氮杂环卡宾类催化剂及其应用，尤其是涉及一种全新结构的、高活性以及高立体选择性的手性氮杂环卡宾类催化剂，以及其在催化不对称Suzuki交叉偶联反应中的应用。
背景技术
Suzuki交叉偶联反应具有反应条件温和，官能团容忍性强，反应产率以及选择性相对较高，反应试剂毒性较小，且对水、空气、热都相对不敏感，反应的后处理简单，适用于工业化生产等优点，从而受到研究者的重视(现代有机反应：金属催化反应，化学工业出版社，2008)。同时，具有手性联芳基结构的天然产物广泛存在于自然界中，目前已有超过数千个被分离报道。其中，诸多天然产物表现出良好的生理活性(例如，Angew.Chem.,Int.Ed.2005,44,5384)，通过不对称催化的手段合成得到这些天然产物的关键手性联芳基结构片段具有重要意义。因此，不对称Suzuki交叉偶联反应现已成为近些年的研究热点。
尽管催化不对称交叉偶联反应已经有了很大的发展，但是目前这一催化反应普遍面临的问题是：催化活性相对较低，底物范围窄，官能团容忍性差，立体选择性不高等。因此，开发一个高活性、高立体选择性、官能团容忍性强的催化体系至关重要。从已有文献来看，多数催化体系官能团容忍性不强，条件苛刻(例如，Chem.Rev.2011,111,563)。为数不多的具有高活性和普适性的催化体系摘录如下：
2005年，美国麻省理工学院的Buchwald小组发展了一个普适性的配体S-Phos，对于大位阻Suzuki-Miyaura偶联反应也具有很好的活性；2008年，该小组将发现的S-Phos，X-Phos应用于偶联反应中，利用手性底物，合成了一系列裂环木脂素、奎尼丁等具生物活性的手性化合物，在合成斯的甘辛时，产率为63％，dr值为87：13(可参见Acc.Chem.Res.2008,41,1461)。
2014年，中国科学院Tang小组发展了一个高活性的联芳基单膦配体，具有较高选择性及反应条件温和等特点，其在催化苯并恶唑啉酮作为底物参与的反应时，ee值高达96％，产率为95％(可参见J.Am.Chem.Soc.2014,136,570)。
授权公告号为CN103418438B的中国发明专利公布了一种氮杂卡宾类钯催化剂及其制备方法和应用，以乙二醛为原料在路易斯酸或者布朗斯特酸参与的条件下合成乙二醛二亚胺，然后与多聚甲醛反应得到氮杂卡宾类配体；同时钯(II)与含碳氮双键的化合物反应得到钯(II)环二聚体；该钯环二聚体与氮杂卡宾类配体配位后得到氮杂卡宾类钯催化剂。与上述对比专利相比，本发明具有以下特点：1)催化剂结构不同，本发明所述的手性氮杂环卡宾类催化剂至少包含有两个手性碳原子，可存在于氮杂环卡宾环上或环的取代基上，而对比专利所报道的氮杂环卡宾环催化剂不含任何手性原子或手性基团；2)催化剂立体选择性差异，本发明所述的手性氮杂环卡宾类催化剂可实现高立体选择性的交叉偶联反应，通过催化剂中的手性原子或手性基团实现立体选择性的控制，同时通过手性原子或手性基团结构的调变，可进一步调节反应的立体选择性，而对比专利报道的氮杂环卡宾环催化剂由于不含任何手性原子或手性基团，因此不具备立体选择性；3)手性联芳基产物的构建，使用本发明所述的手性氮杂环卡宾类催化剂可构建具有轴手性的联芳基化合物，可广泛应用于医药中间体以及天然产物关键中间体的构建中，而对比专利所报道的氮杂环卡宾环催化剂只能合成得到非手性联芳基化合物，应用范围有局限性。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种全新结构的、高活性的、普适性的手性氮杂环卡宾亚胺类钯催化剂，尤其是在Suzuki交叉偶联反应中表现出的高活性、高立体选择性和强官能团容忍性强。
本发明的目的可以通过以下技术方案来实现：
一种手性氮杂环卡宾类催化剂，该催化剂的化学结构式为：
上述分子结构中至少包含有两个手性碳原子，其中，R1、R2、R3、R4分别独立地代表H、烷基、杂烷基或芳基，R5、R6分别独立地代表H、卤素、烷基、杂烷基或芳基，X、Y分别独立地代表含碳原子基团或含杂原子基团，Z代表烷基、杂烷基或芳基，M为过渡金属。
所述的M为钯、铬或镍中的一种。
作为优选的技术方案，所述的R1、R2、R3、R4分别独立地代表H、C1-C15直链或者支链烷基以及C1-C15含氮、氧杂的直链或支链烷基或芳基。
作为进一步优选的技术方案，所述的R1、R2、R3、R4分别独立地代表H、C1-C10直链或者支链烷基以及C1-C10含氮、氧杂的直链或支链烷基或芳基。
所述的R1、R2、R3、R4分别独立地代表甲基、乙基、丙基、异丙基、正丁基、异丁基、1-乙基丙基、环己基、氮二甲基、氮二乙基、甲氧基、乙氧基、1-苯基丙基、4-叔丁基苯基、3,5-二叔丁基苯基、4-甲基苯基、3,5-二甲基苯基、4,4-联苯基、3,5-二(苯基)苯基或萘基。
作为优选的技术方案，所述的R5、R6分别独立地代表H、卤素、C1-C15直链或者支链烷基或芳基。
作为进一步优选的技术方案，所述的R5、R6分别独立地代表H、氯、溴、甲基、乙基、丙基、甲氧基、乙氧基或萘基。
作为优选的技术方案，所述的X、Y分别独立地代表羟基、甲氧基、取代烯基或取代芳基。
作为优选的技术方案，所述的Z代表C1-C10直链或支链烷基、取代或未取代的C6-C18芳基。
作为进一步优选的技术方案，所述的Z代表苯基、1-萘基、4-叔丁基苯基、3,5-二叔丁基苯基、4-甲基苯基、3,5-二甲基苯基、4,4-联苯基或3,5-二(苯基)苯基。
本发明所述的手性氮杂环卡宾类催化剂的制备方法包括以下步骤：
步骤A：以手性胺(Ⅰ)为原料，与1,2-二取代乙二醛在添加剂(Ⅱ)作用下反应生成手性乙二醛二亚胺中间体(Ⅲ)，化学反应结构式如下：
步骤B：式(Ⅲ)所示手性乙二醛二亚胺中间体经过硼氢化钠还原后，与多聚甲醛在添加剂(Ⅵ)的作用环合生成式(Ⅴ)所示的手性氮杂环卡宾类化合物，化学反应结构式如下：
步骤C：式(Ⅴ)所示手性氮杂环卡宾类化合物在添加剂(Ⅵ)作用下同钯(Ⅱ)和式(Ⅶ)反应得到式(Ⅷ)所示的手性氮杂环卡宾类催化剂，化学反应结构式如下：
步骤A中，手性胺(Ⅰ)与1，2-二取代乙二醛在添加剂(Ⅱ)作用下反应生成(Ⅲ)手性乙二醛二亚胺中间体。
所述的添加剂(Ⅱ)为无机盐，选自氯化钠、硫酸钠中的一种。
步骤B中的环合反应由式(Ⅲ)所示手性乙二醛二亚胺中间体与多聚甲醛在添加剂(Ⅵ)的作用下反应。
所述的添加剂(Ⅵ)为盐酸二氧六环溶液或者三甲基氯硅烷，优选三甲基氯硅烷。
步骤C中的配位反应是在隔绝空气的条件下进行，所述的钯(Ⅱ)选自氯化钯、醋酸钯、硝酸钯和乙酰丙酮钯中的一种或者任意两种的混合物，所述的碱(Ⅵ)选自叔丁醇钾、叔丁醇钠、氢氧化钾、乙醇钠、碳酸钾或者醋酸钠中的一种。
一种手性氮杂环卡宾类催化剂的应用，所述的催化剂用于催化不对称Suzuki交叉偶联反应中，在碱的作用下催化不同卤代芳烃与芳基硼酸的不对称Suzuki交叉偶联反应。
本发明手性氮杂环卡宾类催化剂应用于Suzuki-Myaura时，在碱的作用下，催化不同卤代芳烃与芳基硼酸的交叉偶联反应，如式A所示：
式A中产物Ar-Ar'是具有轴手性的化合物，其中，Ar、Ar'分别独立地代表取代或未被取代的C6-C18芳基、C4-C10的氮杂环芳烃、氧杂环芳烃或者硫杂环芳烃。
X1优选Cl或Br。
所述的碱包括叔丁醇钾、叔丁醇钠、氢氧化钾、氢氧化钠、磷酸钾、碳酸钾、碳酸钠或甲醇钠。
与现有技术相比，本发明手性氮杂环卡宾类催化剂至少包含两个手性碳原子，手性碳原子所连接基团充分可调，在Suzuki交叉偶联反应中表现出极高的催化活性性以及立体选择性，是一类新型催化剂，具有以下特点：
1)高活性——本发明催化剂采用了具有不对称结构的氮杂环卡宾作为配体，不仅提高了催化剂活性，加快偶联反应中氧化加成步骤的反应速率，同时得益于氮杂环卡宾配体的特性，还大大提高催化剂对于空气的稳定性，另一方面，采用结构高度可调的辅助配体，通过改变辅助配体上的取代基团，为进一步调节催化剂活性提供可能；
2)普适性——本发明催化剂无论是催化吸电子底物、给电子底物，还是大位阻底物，均能取得不错的收率；
3)高立体选择性——本发明催化剂氮杂环卡宾配体含有多个手性碳原子，且该手性碳原子上所连接的基团高度可调，在催化循环过程中氮杂环卡宾配体上的手性基团能充分保证稳定的立体环境，提高产物的立体选择性。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
实施例1：
(2E,3E)-N2,N3-双((R)-3,3-二甲基丁-2-基)丁-2,3-二胺的合成
在反应器中加入(R)-3,3-二甲基丁-2-胺101g(1mol)，二氯甲烷400mL，再加入1,2-二甲基乙二醛43g(0.5mol)，无水硫酸钠14.1g(0.1mol)，室温搅拌3小时，将反应液过滤，同时用200mL无水甲醇洗涤滤饼，将滤饼干燥至衡重，即可得到目标产物(2E,3E)-N2,N3-双((R)-3,3-二甲基丁-2-基)丁-2,3-二胺。产品为淡黄色固体，229g，产率91％。1HNMR(500MHz,CDCl3):δ3.79(m,2H),2.18(s,6H),1.06(s,6H),1.00(s,18H)。重复上述步骤，制备足够量的(2E,3E)-N2,N3-双((R)-3,3-二甲基丁-2-基)丁-2,3-二胺。
(4S,5S)-1,3-二((R)-3,3-二甲基丁-2-基)-4,5-二甲基咪唑盐酸盐的合成
在反应器中加入(2E,3E)-N2,N3-双((R)-3,3-二甲基丁-2-基)丁-2,3-二胺68g(0.27mol)，1.5L乙酸乙酯，冰水浴加入硼氢化钠10g(0.27mol)，搅拌1h，加入8.1g多聚甲醛(0.27mol)，加热至70℃搅拌均匀，然后缓慢滴加45.8g四氯硅烷(0.27mol)，滴加时间控制在45分钟到1小时，继续搅拌3小时。将反应液过滤，同时用200mL乙酸乙酯洗涤滤饼，将滤饼干燥至衡重，即可得到目标产物(4S,5S)-1,3-二((R)-3,3-二甲基丁-2-基)-4,5-二甲基咪唑盐酸盐。产品为灰白色固体，65g，产率80％。1HNMR(500MHz,CDCl3):δ3.39(m,1H),2.88(m,2H),2.43(m,2H),1.36(s,6H),1.14(s,6H),0.96(s,18H)。重复上述步骤，制备足够量的咪唑盐作为催化剂NHC配体。
(4S,5S)-1,3-二((R)-3,3-二甲基丁-2-基)-4,5-二甲基咪唑钯催化剂的合成
在惰性氛围下，向反应器中加入(4S,5S)-1,3-二((R)-3,3-二甲基丁-2-基)-4,5-二甲基咪唑30.1g(0.1mol)，氯化钯17.7g(0.1mol)，(E)-N,1-二苯基-1-亚胺19.5g(0.1mol)，碳酸钾13.8g(0.1mol)，无水四氢呋喃400mL，加热至80℃，搅拌反应24h，将反应液过滤，用100mL乙酸乙酯洗涤，合并滤液后出去溶剂并干燥即得目标产物NHC-Pd催化剂。产品为亮黄色固体，20g，产率38％。1HNMR(500MHz,CDCl3):δ7.06-7.38(m,9H),2.62(m,2H),2.40(m,2H),2.16(s,3H),1.36(s,6H),1.14(s,6H),1.02(s,18H)。
实施例2：
将实施例1中的(R)-3,3-二甲基丁-2-胺101g(1mol)改为(S)-2,2-二甲基-1-苯基丙烷-1-胺163g(1mol)，其他条件不变，经反应后可得(2E,3E)-N2,N3-双((S)-2,2-二甲基-1-苯基丙基)丁烷-2,3-二胺323g，产率86％。1HNMR(500MHz,CDCl3):δ7.29-7.37(m,10H),5.45(s,2H),2.19(s,6H),1.04(s,18H)。
利用反应得到的(2E,3E)-N2,N3-双((S)-2,2-二甲基-1-苯基丙基)丁烷-2,3-二胺与多聚甲醛在四氯硅烷作用下得到(4S，5S)-1,3-双((S)-2,2-二甲基-1-苯基丙基)-4,5-二甲基咪唑盐酸盐。1HNMR(500MHz,CDCl3):δ7.24-7.32(m,10H),3.61(s,2H),3.39(m,2H),2.58(m,2H),1.44(s,6H)。1.01(s,18H)。。
在惰性氛围下，将实施例1中的(4S,5S)-1,3-二((R)-3,3-二甲基丁-2-基)-4,5-二甲基咪唑30.1g(0.1mol)改为加入42.9g(0.1mol)(4S,5S)-1,3-双((S)-2,2-二甲基-1-苯基丙基)-4,5-二甲基咪唑盐酸盐，其余条件不变，经反应后得到产品为亮黄色固体，31g，产率47％。1HNMR(500MHz,CDCl3):δ7.06-7.47(m,19H),3.65(s,2H),2.48(m,2H),2.23(s,3H),1.36(s,6H),1.02(s,18H)。
在Suzuki-Myaura偶联反应中的应用：
实施例3：
在惰性氛围下，向反应器中加入12.6g邻氯甲苯(0.1mol)，12.2g苯硼酸(0.1mol)，8.4g氢氧化钾(0.15mol)以及0.005mol不对称氮杂环卡宾亚胺类钯催化剂，以及10mL异丙醇。在80℃条件下搅拌4小时后停止反应。除去反应液的溶剂，得到粗产品，气相产率>99％。柱层析纯化得到目标产物15.6g，分离产率92％，ee值为81％。
1HNMR(500MHz,CDCl3):δ7.41(t,J＝7.5Hz,2H),7.31-7.35(m,3H),7.23-7.25(m,4H),2.27(s,3H)。
实施例4：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为18.0g对氯三氟甲苯(0.1mol)，其他条件不变，柱层析纯化得到目标产物22.1g，分离产率99％，ee值为78％。
1HNMR(400MHz,CDCl3):δ8.04(d,J＝8.4Hz,2H),7.69(d,J＝8.4Hz,2H),7.63(d,J＝7.2Hz,2H),7.48(t,J＝7.4Hz,2H),7.40(t,J＝7.2Hz,1H),2.64(s,3H)。
实施例5：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为14.0g2-氯间二甲苯(0.1mol)，其他条件不变，柱层析纯化得到目标产物17.5g，分离产率96％，ee值为60％。
1HNMR(500MHz,CDCl3):δ7.54–7.36(m,6H),7.21(d,J＝7.5Hz,2H),2.56(s,6H)。
实施例6：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为15.4g对氯苯乙酮(0.1mol)，其他条件不变，柱层析纯化得到目标产物19.0g，分离产率97％，ee值为78％。
1HNMR(500MHz,CDCl3):δ8.04(d,J＝8.4Hz,2H),7.69(d,J＝8.4Hz,2H),7.63(d,J＝7.2Hz,2H),7.48(t,J＝7.4Hz,2H),7.40(t,J＝7.2Hz,1H),2.64(s,3H)。
实施例7：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为14.2g邻氯苯甲醚(0.1mol)，其他条件不变，柱层析纯化得到目标产物19.0g，分离产率99％，ee值为91％。
1HNMR(400MHz,CDCl3):δ7.52(d,J＝9.6Hz,2H),7.40(t,J＝7.4Hz,2H),7.31(t,J＝6.6Hz,3H),6.96-7.04(m,2H),3.78(s,3H)。
实施例8：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为16.2g1-氯萘(0.1mol)，其他条件不变，柱层析纯化得到目标产物16.7g，分离产率80％，ee值为72％。
1HNMR(500MHz,CDCl3):δ7.89(d,J＝8.5Hz,2H),7.84(d,J＝8.5Hz,1H),7.40-7.52(m,9H)。
实施例9：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为21.2g9-氯蒽(0.1mol)，其他条件不变，柱层析纯化得到目标产物23.4g，分离产率92％，ee值为91％。
1HNMR(500MHz,CDCl3):δ8.50(s,1H),8.05(d,J＝8.5Hz,2H),7.66(d,J＝8.5Hz,2H),,7.55(d,J＝7.5Hz,2H),7.54(d,J＝6.5Hz,1H),7.43-7.47(m,4H),7.26-7.36(m,2H)。
实施例10：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为11.3g3-氯吡啶(0.1mol)，其他条件不变，柱层析纯化得到目标产物15.2g，分离产率99％，ee值为90％。
1HNMR(500MHz,CDCl3):δ8.85(d,J＝2.0Hz,1H),8.59(dd,J＝1.5Hz,4.5Hz,1H),7.86(dd,J＝4.5Hz,8.0Hz,1H),7.58(d,J＝8.0Hz,2H),7.35-7.49(m,4H)。
实施例11：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为11.3g2-氯吡啶(0.1mol)，其他条件不变，柱层析纯化得到目标产物15.3g，分离产率99％，ee值为92％。
1HNMR(500MHz,CDCl3):δ8.69-8.71(m,1H),7.98-8.00(m,2H),7.72-7.77(m,2H),7.40-7.50(m,3H),7.22-7.25(m,1H)。
实施例12：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为11.8g2-氯噻吩(0.1mol)，其他条件不变，柱层析纯化得到目标产物15.8g，分离产率99％，ee值为80％。
1HNMR(500MHz,CDCl3):δ7.61(d,J＝7.5Hz,2H),7.26-7,38(m,5H),7.07(dd,J＝4.0Hz,5.0Hz,1H)。
实施例13：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为13.0g5-氟-2-氯吡啶(0.1mol)，其他条件不变，柱层析纯化得到目标产物17.1g，分离产率99％，ee值为90％。
1HNMR(500MHz,CDCl3):δ8.42(d,J＝1.5Hz,1H),7.96-7.98(m,1H),7.53-7.55(m,2H),7.47-7.49(m,2H),7.41(t,J＝5.0Hz,1H),7.01(dd,J＝2.5Hz,6.5Hz,1H)。
实施例14：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为22.1g1-溴-2-甲基萘(0.1mol)，其他条件不变，柱层析纯化得到目标产物18.5g，分离产率85％，ee值为90％。
1HNMR(500MHz,CDCl3):δ7.90-7.98(m,3H),7.35-7.56(m,8H),2.28(s,3H)。
实施例15：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为22.1g1-溴-2-甲基萘(0.1mol)，12.2g苯硼酸(0.1mol)改为17.2g萘硼酸(0.1mol)，其他条件不变，柱层析纯化得到目标产物11.2g，分离产率42％，er值为88.5：11.5。
1HNMR(500MHz,CDCl3):δ7.97-8.00(m,2H),7.90-7.92(m,2H),7.40-7.66(m,7H),7.22-7.33(m,1H),7.17-7.19(m,1H),2.14(s,3H)。
实施例16：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为23.7g1-溴-2-甲氧基萘(0.1mol)，12.2g苯硼酸(0.1mol)改为19.8g联苯基-2-硼酸(0.1mol)，其他条件不变，柱层析纯化得到目标产物15.5g，分离产率50％，er值为52：48。
1HNMR(500MHz,CDCl3):δ7.78(d,J＝12.5Hz,1H),7.62-7.64(m,4H),7.28-7.41(m,3H),7.12(d,J＝12.5Hz,1H),6.96-7.08(m,4H),3.52(s,3H)。
实施例17：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为22.1g1-溴-2-甲基萘(0.1mol)，12.2g苯硼酸(0.1mol)改为19.8g联苯基-2-硼酸(0.1mol)，其他条件不变，柱层析纯化得到目标产物17.6g，分离产率60％，er值为61.5：38.5。
1HNMR(500MHz,CDCl3):δ7.81(d,J＝10Hz,1H),7.69(d,J＝10Hz,1H),7.53-7.57(m,4H),7.48-7.50(m,2H),7.40(m,1H),7.29(d,J＝10Hz,1H),7.02-7.06(m,5H),2.01(s,3H)。
实施例18：
将实施例1中所加入的12.6g邻氯甲苯(0.1mol)改为23.7g1-溴-2-甲氧基萘(0.1mol)，12.2g苯硼酸(0.1mol)改为17.2g萘硼酸(0.1mol)，其他条件不变，柱层析纯化得到目标产物25.0g，分离产率88％，er值为91：9。
1HNMR(500MHz,CDCl3):δ7.99(d,J＝12.5Hz,1H),7.86(dd,J＝10Hz,5.0Hz,2H),7.87(d,J＝10Hz,1H),7.87(dd,J＝10Hz,7.75Hz,1H),7.40-7.50(m,3H),7.27-7.36(m,3H),7.19-7.25(m,1H),7.15(d,J＝12.5Hz,1H),3.77(s,3H)。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于上述实施例，本领域技术人员根据本发明的揭示，不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (10)
1.一种手性氮杂环卡宾类催化剂，其特征在于，该催化剂的化学结构式为：
上述分子结构中至少包含有两个手性碳原子，其中，R1、R2、R3、R4分别独立地代表H、烷基、杂烷基或芳基，R5、R6分别独立地代表H、卤素、烷基、杂烷基或芳基，X、Y分别独立地代表含碳原子基团或含杂原子基团，Z代表烷基、杂烷基或芳基，M为过渡金属。
2.根据权利要求1所述的一种手性氮杂环卡宾类催化剂，其特征在于，所述的M为钯、铬或镍中的一种。
3.根据权利要求1所述的一种手性氮杂环卡宾类催化剂，其特征在于，所述的R1、R2、R3、R4分别独立地代表H、C1-C15直链或者支链烷基以及C1-C15含氮、氧杂的直链或支链烷基或芳基。
4.根据权利要求3所述的一种手性氮杂环卡宾类催化剂，其特征在于，所述的R1、R2、R3、R4分别独立地代表H、C1-C10直链或者支链烷基以及C1-C10含氮、氧杂的直链或支链烷基或芳基。
5.根据权利要求4所述的一种手性氮杂环卡宾类催化剂，其特征在于，所述的R1、R2、R3、R4分别独立地代表甲基、乙基、丙基、异丙基、正丁基、异丁基、1-乙基丙基、环己基、氮二甲基、氮二乙基、甲氧基、乙氧基、1-苯基丙基、4-叔丁基苯基、3,5-二叔丁基苯基、4-甲基苯基、3,5-二甲基苯基、4,4-联苯基、3,5-二(苯基)苯基或萘基。
6.根据权利要求1所述的一种手性氮杂环卡宾类催化剂，其特征在于，所述的R5、R6分别独立地代表H、卤素、C1-C15直链或者支链烷基或芳基。
7.根据权利要求6所述的一种手性氮杂环卡宾类催化剂，其特征在于，所述的R5、R6分别独立地代表H、氯、溴、甲基、乙基、丙基、甲氧基、乙氧基或萘基。
8.根据权利要求1所述的一种手性氮杂环卡宾类催化剂，其特征在于，所述的X、Y分别独立地代表羟基、甲氧基、取代烯基或取代芳基，所述的Z代表C1-C10直链或支链烷基、取代或未取代的C6-C18芳基。
9.根据权利要求8所述的一种手性氮杂环卡宾类催化剂，其特征在于，所述的Z代表苯基、1-萘基、4-叔丁基苯基、3,5-二叔丁基苯基、4-甲基苯基、3,5-二甲基苯基、4,4-联苯基或3,5-二(苯基)苯基。
10.如权利要求1至9任一项所述的一种手性氮杂环卡宾类催化剂的应用，其特征在于，所述的催化剂用于催化不对称Suzuki交叉偶联反应中，在碱的作用下催化不同卤代芳烃与芳基硼酸的不对称Suzuki交叉偶联反应。
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