CN114685564B - 新型亚磷酰胺配体及其合成方法和应用 - Google Patents
新型亚磷酰胺配体及其合成方法和应用 Download PDFInfo
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- CN114685564B CN114685564B CN202011572171.3A CN202011572171A CN114685564B CN 114685564 B CN114685564 B CN 114685564B CN 202011572171 A CN202011572171 A CN 202011572171A CN 114685564 B CN114685564 B CN 114685564B
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- substituted
- aryl
- substituent
- alkyl
- heteroaryl
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- 239000003446 ligand Substances 0.000 title abstract description 28
- 150000008300 phosphoramidites Chemical class 0.000 title abstract description 14
- 238000001308 synthesis method Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 150000001336 alkenes Chemical class 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- -1 aryl boric acid Chemical compound 0.000 claims description 54
- 125000001424 substituent group Chemical group 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- 125000003107 substituted aryl group Chemical group 0.000 claims description 22
- 125000004423 acyloxy group Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 10
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 10
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 10
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 8
- 238000007038 hydrochlorination reaction Methods 0.000 claims description 7
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 6
- 125000004442 acylamino group Chemical group 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004327 boric acid Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 2
- 125000004641 (C1-C12) haloalkyl group Chemical group 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 claims description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 230000014759 maintenance of location Effects 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- 239000011521 glass Substances 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 229920002160 Celluloid Polymers 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 238000004896 high resolution mass spectrometry Methods 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 239000007791 liquid phase Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
- 239000003517 fume Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000003480 eluent Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000005810 carbonylation reaction Methods 0.000 description 5
- 125000004185 ester group Chemical group 0.000 description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 3
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 3
- 229960002390 flurbiprofen Drugs 0.000 description 3
- 229960001680 ibuprofen Drugs 0.000 description 3
- 229960002009 naproxen Drugs 0.000 description 3
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 2
- VTMSSJKVUVVWNJ-UHFFFAOYSA-N 1-ethenyl-4-(2-methylpropyl)benzene Chemical compound CC(C)CC1=CC=C(C=C)C=C1 VTMSSJKVUVVWNJ-UHFFFAOYSA-N 0.000 description 2
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 2
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 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
- 150000007513 acids Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- DLIJPAHLBJIQHE-UHFFFAOYSA-N butylphosphane Chemical compound CCCCP DLIJPAHLBJIQHE-UHFFFAOYSA-N 0.000 description 2
- 238000006473 carboxylation reaction Methods 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229960001419 fenoprofen Drugs 0.000 description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 2
- 229960000991 ketoprofen Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- 229940080818 propionamide Drugs 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- MNJYZNVROSZZQC-UHFFFAOYSA-N (4-tert-butylphenyl)boronic acid Chemical compound CC(C)(C)C1=CC=C(B(O)O)C=C1 MNJYZNVROSZZQC-UHFFFAOYSA-N 0.000 description 1
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- WKBALTUBRZPIPZ-UHFFFAOYSA-N 2,6-di(propan-2-yl)aniline Chemical compound CC(C)C1=CC=CC(C(C)C)=C1N WKBALTUBRZPIPZ-UHFFFAOYSA-N 0.000 description 1
- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- NTYHSGAJVIGSEY-UHFFFAOYSA-N 4-ethenyl-2-fluoro-1-phenylbenzene Chemical compound FC1=CC(C=C)=CC=C1C1=CC=CC=C1 NTYHSGAJVIGSEY-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920005479 Lucite® Polymers 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- UCIPLLNDFCCBAC-UHFFFAOYSA-N [4-(2-methylpropoxy)phenyl]boronic acid Chemical compound CC(C)COC1=CC=C(B(O)O)C=C1 UCIPLLNDFCCBAC-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001278 adipic acid derivatives Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
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- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960002373 loxoprofen Drugs 0.000 description 1
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 description 1
- VUZPPFZMUPKLLV-UHFFFAOYSA-N methane;hydrate Chemical compound C.O VUZPPFZMUPKLLV-UHFFFAOYSA-N 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 125000001209 o-nitrophenyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])[N+]([O-])=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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Abstract
本发明公开了结构通式(I)和(II)所示的化合物及其制备方法和应用,本发明方法原料易得、反应条件温和、产物易于分离提纯。所合成的新型亚磷酰胺配体可以有效应用于烯烃的不对称氢羰基化反应,能以高的对映选择性、区域选择性和高的产率得到产物。
Description
技术领域
本发明涉及一类新型亚磷酰胺配体及其合成方法和应用,属于不对称有机合成技术领域。
背景技术
钯催化烯烃与一氧化碳的氢羰基化反应是合成含羰基化合物最直接、高效的方法之一,并已经被广泛应用于多种酯、酸、酰胺的合成。钯催化乙烯与一氧化碳和醇的氢酯基化反应已经被Lucite公司用于丙酸甲酯的工业合成,钯催化丁二烯与一氧化碳和醇的氢酯基化反应被用于己二酸酯的合成,钯催化烯烃与一氧化碳和水的氢羧酸化反应被应用于脂肪酸的合成,钯催化烯烃与一氧化碳和胺的氢酰胺化反应被用于酰胺的合成。上述反应过程均不能很好的实现反应的对映选择性控制。
在过去的几十年中,钯催化烯烃的氢羰基化反应已经取得重要的进展,但是由于反应过程十分复杂且该类型反应在工业生产中具有广泛而重要的应用前景,关于该类型反应仍然存在许多悬而未决的科学和技术难题。特别是由于一氧化碳本身具有非常强的配位性,仍然缺乏有效的、可用于该类反应的手性配体,对映选择性控制一直是该类反应中最重要的难题之一。
发明内容
本发明的目的是提供一类可用于钯催化不对称氢羰基化反应的新型亚磷酰胺配体及其合成方法,使用本发明新型亚磷酰胺配体可实现α-取代的手性丙酸、α-取代的手性丙酸酯和α-取代的手性丙酰胺的不对称合成,为光学纯布洛芬、萘普生、酮洛芬、非诺洛芬、氟比洛芬等芳基丙酸类非甾体抗炎药的不对称合成提供新方法。
本发明实现过程如下:
结构通式(I)和(II)所示的化合物,
R1选自C6~C24的芳基或取代芳基,所述取代芳基中的取代基为C1~C12的烷基、C1~C6的烷氧基、C1~C6的烷基氨基、卤素基、硝基、氰基、C1~C12的卤代烷基、C6~C18的芳基;
R2和R3独立地选自氢、C1~C6的烷基、C1~C6的卤代烷基、C1~C6的烷氧基、卤素基、C6~C18的芳基、硝基、氰基;
X选自氧、硫、、、、、、,
R4和R5独立地选自氢、C1-C6的烷基、C1-C6的烷氧基、C6~C12的芳基;
R6选自C1-C6的烷基、C6~C12的芳基或取代的芳基,所述取代芳基中的取代基为C1~C6的烷基、C1~C6的烷氧基、卤素基、酯基、硝基。
具体来说,上述R1可选自苯基、对甲基苯基、间甲基苯基、邻甲基苯基、2,4-二甲基苯基、3,4-二甲基苯基、3,5-二甲基苯基、2,6-二甲基苯基、2,4,6-三甲基苯基、对乙基苯基、间乙基苯基、邻乙基苯基、对异丙基苯基、对叔丁基苯基、间叔丁基苯基、邻叔丁基苯基、对羟基苯基、对甲氧基苯基、间甲氧基苯基、邻甲氧基苯基、2,6-二甲氧基苯基、3,5-二甲氧基苯基、对乙氧基苯基、间乙氧基苯基、邻乙氧基苯基、对正丙氧基苯基、对异丙氧基苯基、对正丁氧基苯基、对异丁氧基苯基、间异丁氧基苯基、邻异丁氧基苯基、对叔丁氧基苯基、对正辛氧基苯基、对苯氧基苯基、对苄氧基苯基、对氟苯基、间氟苯基、邻氟苯基、2,4-二氟苯基、2,6-二氟苯基、3,5-二氟苯基、对氯苯基、间氯苯基、邻氯苯基、2,4-二氯苯基、2,6-二氯苯基、3,5-二氯苯基、对溴苯基、对三氟甲基苯基、间三氟甲基苯基、邻三氟甲基苯基、3,5-二三氟甲基苯基、2,6-二三氟甲基苯基、对硝基苯基、间硝基苯基、邻硝基苯基、对氰基苯基、对羧基苯基、对甲酯基苯基、对乙酯基苯基、对苯基苯基、3,5-二苯基苯基、1-萘基、2-萘基、9-蒽基、9-菲基、1-芘、对-(2-萘)苯基、对-(1-萘)苯基、间-(2-萘)苯基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基。
上述化合物(I)的制备方法,包括以下步骤:
(a)将化合物A1或化合物A2,与芳基硼酸在钯催化下发生Suzuki偶联反应分别得到化合物B1或B2;
(b)将化合物C与三氯化磷反应得到化合物D;
(c)将化合物D与化合物B1或B2反应得到化合物(I)或(II);
。
上述化合物在烯烃的不对称氢氨羰基化反应中的应用,
R7 选自氢、C1-C16的烷基或取代烷基、C1-C16的烷氧基或取代烷氧基、C1-C6的酰氧基或取代酰氧基、C1-C16的酯基或取代酯基、C2-C12的烯基或炔基、C6~C16的芳基或取代的芳基、C3~C16的杂芳基或取代的杂芳基、二茂铁基或取代的二茂铁基、氨基、氰基,
所述的杂芳基为氮杂芳基、氧杂芳基、硫杂芳基,
所述取代烷基中的取代基、取代烷氧基中的取代基、取代酰氧基中的取代基、取代酯基中的取代基、取代芳基中的取代基、取代杂芳基中的取代基和取代二茂铁基中的取代基为C1~C8的烷基、C1~C6的卤代烷基、C1~C6的烷氧基、C1~C6的酰氧基、C1~C6的酰氨基、C1~C6的烷基氨基、卤素基、酯基、硝基、羟基、氰基;
R8和R9独立地选自氢、C1-C16的烷基或取代烷基、C1~C16的卤代烷基、C2-C12的烯基或炔基、C6~C16的芳基或取代的芳基、C3~C16的杂芳基或取代的杂芳基、二茂铁基或取代的二茂铁基,
所述的杂芳基为氮杂芳基、氧杂芳基、硫杂芳基,
所述取代烷基中的取代基、取代芳基中的取代基、取代杂芳基中的取代基和取代二茂铁基中的取代基为C1~C6的烷基、C1~C6的卤代烷基、C1~C6的烷氧基、C1~C6的酰氧基、C1~C6的酰氨基、C1~C6的烷基氨基、卤素基、羟基、酯基、硝基、氰基。
上述化合物在烯烃的不对称氢酯化或氢羧酸化反应中的应用,
R7 选自氢、C1-C16的烷基或取代烷基、C1-C16的烷氧基或取代烷氧基、C1-C6的酰氧基或取代酰氧基、C1-C16的酯基或取代酯基、C2-C12的烯基或炔基、C6~C16的芳基或取代的芳基、C3~C16的杂芳基或取代的杂芳基、二茂铁基或取代的二茂铁基、氨基、氰基,
所述的杂芳基为氮杂芳基、氧杂芳基、硫杂芳基,
所述取代烷基中的取代基、取代烷氧基中的取代基、取代酰氧基中的取代基、取代酯基中的取代基、取代芳基中的取代基、取代杂芳基中的取代基和取代二茂铁基中的取代基为C1~C8的烷基、C1~C6的卤代烷基、C1~C6的烷氧基、C1~C6的酰氧基、C1~C6的酰氨基、C1~C6的烷基氨基、卤素基、酯基、硝基、羟基、氰基;
R10选自氢、C1-C16的烷基或取代烷基、C1~C16的卤代烷基、C6~C16的芳基或取代的芳基,
所述取代烷基中的取代基和取代芳基中的取代基为C1~C6的烷基、C1~C6的卤代烷基、C1~C6的烷氧基、C2-C6的烯基或炔基、C1~C6的酰氧基、C1~C6的酰氨基、C1~C6的烷基氨基、卤素基、酯基、硝基、氰基。
上述反应体系需要加入酸,酸的加入量为钯催化剂的1~5倍摩尔量,所述的酸为盐酸、硫酸、氢溴酸、氢碘酸、三氟乙酸、对甲苯磺酸、硼酸、特戊酸。
在上述化合物的不对称氢氨羰基化、不对称氢酯化或氢羧酸化反应中,所述的钯催化剂为Pd2(dba)3、Pd(dba)2、醋酸钯、三氟乙酸钯、氯化钯、溴化钯以及碘化钯。
在上述化合物的不对称氢氨羰基化、不对称氢酯化或氢羧酸化反应中,所述的一氧化碳压力为20~50个大气压。
在上述化合物的不对称氢氨羰基化、不对称氢酯化或氢羧酸化反应中,反应在有机溶剂中进行,所述的有机溶剂为乙醚、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、苯甲醚、乙二醇二甲醚、甲基叔丁基醚。
在上述化合物的不对称氢氨羰基化、不对称氢酯化或氢羧酸化反应中,所述的反应温度为0 oC~60 oC。
在上述化合物的不对称氢氨羰基化、不对称氢酯化或氢羧酸化反应中,可合成得到如下产物:
。
在钯催化不对称氢羰基化反应中,反应的区域选择性主要由配体进行调控,通常情况下利用单齿配体易于得到支链产物。烯烃的不对称氢羰基化反应需要在支链选择性的基础上,同时实现反应的对映选择性控制,因此,理论上该类反应需要单齿手性配体来实现。然而,由于一氧化碳具有很强的配位性,现有的单齿配体与羰基化催化体系不能兼容,不能有效控制反应的对映选择性。
本发明的优点与积极效果:本发明设计合成的新型亚磷酰胺配体实现了钯催化烯烃与一氧化碳的不对称氢羰基化反应。运用该不对称氢羰基化反应的策略高效的合成了α-取代的手性丙酸、α-取代的手性丙酸酯和α-取代的手性丙酰胺,以及光学纯的布洛芬、萘普生、酮洛芬、非诺洛芬、氟比洛芬、洛索洛芬等芳基丙酸类非甾体抗炎药。
具体实施方式
以下通过实例对上述本发明的内容作进一步的详细说明,但本发明不局限于列举的实例。下列实例中未注明具体条件的实验方法,按照常规方法和条件实施。
本发明配体的制备方法
实施例1
过程a: 在100毫升的圆底烧瓶中加入3,3-二碘代八氢联萘酚 (3.0毫摩尔, 1.0当量), 对叔丁基苯硼酸(9.0毫摩尔, 3.0当量)、醋酸钯(0.15毫摩尔, 5.0 mol%), 二金刚烷正丁基膦(0.15毫摩尔, 5.0 mol%),然后再加入1,4-二氧六环30.0毫升和浓度为1摩尔/升的碳酸钾水溶液20毫升。将反应置于95oC的油浴中在氩气氛围下搅拌12小时之后冷却至室温。向反应中加入20毫升水后用乙酸乙酯萃取两次。合并有机层,用无水硫酸钠干燥后减压浓缩。粗产品经柱色谱分离得到化合物E1(石油醚:乙酸乙酯= 50 : 1,体积比),产率98%,产量1.64克;
过程b: 在25毫升的圆底烧瓶中将吩噁嗪(1.0毫摩尔, 1.0当量)溶于10毫升的四氢呋喃中,依次加入三氯化磷(1.2毫摩尔, 1.2当量)和三乙胺(4.0毫摩尔, 4.0当量),70oC搅拌2小时得到化合物F;
过程c: 将上述含有化合物F的反应液冷却至0oC,然后向其中滴入E1(1.0毫摩尔,1.0当量)的四氢呋喃溶液(5毫升四氢呋喃),并将该混合物加热回流2小时。反应冷却至室温后用乙酸乙酯萃取,水洗涤。有机层经过干燥,减压浓缩后,柱色谱分离得到亚磷酰胺配体(L5)716毫克,产率93%;
L5:白色固体,1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.30-7.20 (m,6H), 7.17 (s, 1H), 7.09 (s, 1H), 6.80 (td, J = 7.6, 1.6 Hz, 2H), 6.77-6.68(m, 2H), 6.48 (td, J = 7.6, 1.6 Hz, 2H), 5.60 (s,2H), 2.96-2.83 (m, 4H),2.79-2.68 (m, 2H), 2.58-2.38 (m, 2H), 2.11-1.76 (m, 6H), 1.77-1.64 (m, 2H),1.28 (d, J = 7.0 Hz, 18H). 高分辨质谱(ESI电离源), m/z C52H52NNaO3P: [M+Na]+的理论值:792.3577,实测值:792.3572。
实施例2
过程a: 在100毫升的圆底烧瓶中依次加入3,3-二溴代八氢联萘酚(3.0毫摩尔,1.0当量), 对异丁氧基苯硼酸(9.0毫摩尔, 3.0当量)、醋酸钯(0.15毫摩尔, 5.0 mol%),二金刚烷正丁基膦(0.15毫摩尔, 5.0 mol%),然后再加入1,4-二氧六环30毫升和碳酸钾水溶液20毫升(浓度为1摩尔/升)。将反应置于95oC的油浴中在氩气氛围下搅拌12小时之后冷却至室温。向反应中加入20毫升水后用乙酸乙酯萃取两次(每次30毫升)。合并有机层,用无水硫酸钠干燥后减压浓缩。粗产品经柱色谱分离得到化合物E2(石油醚:乙酸乙酯= 50 :1,体积比),产率96%,产量1.70克;
过程b: 在25毫升的圆底烧瓶中将吩噁嗪(1.0毫摩尔, 1.0当量)溶于10毫升的四氢呋喃中,依次加入三氯化磷(1.2毫摩尔, 1.2当量)和三乙胺(4.0毫摩尔, 4.0当量),70oC搅拌2小时得到化合物F;
过程c: 将上述含有化合物F的反应液冷却至0oC,然后向其中滴入E2(1.0毫摩尔,1.0当量)的四氢呋喃溶液(5毫升四氢呋喃),并将该混合物加热回流2小时。反应冷却至室温后用乙酸乙酯萃取,水洗涤。有机层经过干燥,减压浓缩后,柱色谱分离得到亚磷酰胺配体(L9)729毫克,产率91%;
L9:白色固体:1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.4 Hz, 2H), 7.18(d, J = 8.4 Hz, 2H), 7.14 (s, 1H), 7.08 (s, 1H), 6.81-6.75 (m, 6H), 6.69 (d,J = 8.4 Hz, 2H), 6.49 (t, J = 7.6 Hz, 2H), 5.54 (s, 2H), 3.66 (d, J = 6.4 Hz,2H), 3.64-3.62 (m, 1H), 3.56-3.52 (m, 1H), 2.93-2.82 (m, 4H), 2.77-2.71 (m,2H), 2.54-2.43 (m, 2H), 2.06-2.01 (m, 2H), 1.95-1.80 (m, 6H), 1.70-1.68 (m,2H), 1.02-0.97 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 158.6, 158.4, 149.6,144.69, 144.65, 143.9, 137.0, 134.6, 134.2, 132.2, 131.41, 131.39, 130.9,130.7, 130.5, 130.44, 130.42, 130.2, 130.12, 130.11, 130.06, 130.0, 129.4,124.0, 122.6, 115.5, 114.1, 114.0, 74.3, 74.2, 29.3, 29.1, 28.3, 28.2, 27.9,27.7, 23.0, 22.88, 22.86, 22.7, 19.3. 高分辨质谱(ESI电离源), m/z C52H52NNaO5P:[M+Na]+的理论值:824.3475,实测值:824.3482;
与L9合成方法类似,可得到L10,
L10:白色固体,1H NMR (400 MHz, CDCl3) δ 7.41-7.29 (m, 2H), 7.26-7.17(m, 2H), 7.17 (s, 1H), 7.11 (s, 1H), 6.89-6.76 (m, 6H), 6.78-6.70 (m, 2H),6.59-6.47 (m, 2H), 5.54 (s, 2H), 4.00-3.64 (m, 2H), 2.97-2.86 (m, 4H), 2.84-2.68 (m, 2H), 2.63-2.45 (m, 2H), 2.05-1.84 (m, 6H), 1.83-1.67 (m, 14H). 高分辨质谱(ESI电离源), m/z C50H48NNaO5P: [M+Na]+的理论值:796.3162,实测值:796.3168;
与L9合成方法类似,可得到L11,
L11:白色固体,1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.8 Hz, 2H), 7.18(d, J = 8.8 Hz, 2H), 7.14 (s, 1H), 7.08 (s, 1H), 6.88-6.74 (m, 6H), 6.73-6.67(m, 2H), 6.51-6.47 (m, 2H), 5.56 (s, 2H), 4.05-3.70 (m, 4H), 2.95-2.84 (m,4H), 2.79-2.67 (m, 2H), 2.58-2.37 (m, 2H), 1.99-1.79 (m, 6H), 1.78-1.64 (m,6H), 1.53-1.38 (m, 4H), 0.96 (dt, J = 13.6, 7.4 Hz, 6H). 高分辨质谱(ESI电离源), m/z C52H52NNaO5P: [M+Na]+的理论值:824.3475,实测值:824.3479。
本发明亚磷酰胺配体的合成原料易得、步骤简单、条件温和、产率高。按照实施例1-2的合成步骤,仅改变芳基硼酸和胺源的类型,可以容易的合成出表1所示的配体L1 ~L30,但表1所示的配体并不以任何形式限定本发明专利的范围。
表 1 本发明合成得到的亚磷酰胺配体
本发明配体在钯催化不对称氢氨羰基化反应中的应用
实施例3:向5.0毫升玻璃瓶中加入苯乙烯(0.15毫摩尔,1.5当量),2,6-二异丙基苯胺(0.1毫摩尔,1.0当量),PdI2(0.01毫摩尔,10mol%),L9(0.011毫摩尔,11mol%)和四氢呋喃(1.0毫升)。将玻璃瓶放入高压釜中,加压至50个大气压的CO之后室温搅拌72 小时。然后将高压釜中的CO小心地释放到通风良好的通风橱中。通过GC-MS分析粗产物确定支链酰胺:直链酰胺> 99:1。反应混合物通过柱色谱分离得到3g,洗脱剂:石油醚和乙酸乙酯(10:1,体积比);
白色固体,产率62%,93% ee;[α]D20 = -23.6 (c = 1.8, CHCl3). 1H NMR (600MHz, CDCl3) δ 7.44-7.39 (m, 4H), 7.33-7.31 (m, 1H), 7.25-7.21 (m, 1H), 7.09(d, J = 7.8 Hz, 2H), 6.45 (s, 1H), 3.83 (q, J = 7.2 Hz, 1H), 2.80 (m, 2H),1.66 (d, J = 7.2 Hz, 3H), 1.07 (d, J = 6.6 Hz, 12H); 13C NMR (151 MHz, CDCl3)δ 173.3, 146.1, 141.2, 131.2, 129.0, 128.1, 127.6, 127.5, 123.2, 47.4, 28.5,23.4, 23.3, 17.7. 高效液相测试条件:大赛璐手性IF柱(规格:4.6x250 mm),进样量:5 μL,柱温箱:30℃,流动相极性:正己烷/异丙醇=85/15,流速: 1.0毫升/分钟,紫外灯波长:254 nm,保留时间(多) = 4.57分钟, 保留时间(少) = 5.26分钟。
实施例4:向5.0毫升玻璃瓶中加入苯乙烯(0.3毫摩尔,1.5当量),对氨基酚(0.2毫摩尔,1.0当量),PdI2(0.02毫摩尔,10mol%),L5(0.022毫摩尔,11mol%)和四氢呋喃(2.0毫升)。将玻璃瓶放入高压釜中,加压至60个大气压的CO之后室温搅拌72 小时。然后将高压釜中的CO小心地释放到通风良好的通风橱中。通过GC-MS分析粗产物确定支链酰胺:直链酰胺> 99:1。反应混合物通过柱色谱分离得到3l,洗脱剂:石油醚和乙酸乙酯(10:1,体积比);
白色固体,产率75%,89%ee;[α]D18 = -106.8 (c = 0.6, CHCl3). 1H NMR (400MHz, d 6 -DMSO) δ 9.78 (s, 1H), 9.15 (s, 1H), 7.38-7.29 (m, 6H), 7.22 (t, J =7.2 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 3.76 (q, J = 7.2 Hz, 1H), 1.39 (d, J =7.2 Hz, 3H); 13C NMR (101 MHz, d 6 -DMSO) δ 171.4, 153.2, 142.1, 130.9, 128.3,127.2, 126.6, 120.8, 115.0, 45.7, 18.7. 高效液相测试条件:大赛璐手性IB N-5柱(规格:4.6x250 mm),进样量:5 μL,柱温箱:30℃,流动相极性:正己烷/异丙醇=85/15,流速: 1.0毫升/分钟,紫外灯波长:254 nm,保留时间(多) = 14.47分钟, 保留时间(少) =20.60分钟;
与化合物3l合成方法类似,仅改变底物可合成得到如下两个化合物:
白色固体,产率98%,90%ee;[α] D16 = +42.0 (c = 1.7, CHCl3). 1H NMR (400MHz, CDCl3) δ 7.42 (d, J = 8.0 Hz, 2H), 7.34 (s, 1H), 7.26-7.22 (m, 4H), 7.13(d, J = 7.6 Hz, 2H), 7.04 (t, J = 7.6 Hz, 1H), 3.69 (q, J = 7.2 Hz, 1H), 2.46(d, J = 7.2 Hz, 2H), 1.90-1.80 (m, 1H), 1.56 (d, J = 7.2 Hz, 3H), 0.90 (d, J= 6.4 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 172.7, 140.9, 138.0, 137.9, 129.7,128.8, 127.3, 124.1, 119.7, 47.6, 44.9, 30.1, 22.3, 18.5. 高效液相测试条件:大赛璐手性IG柱(规格:4.6x250 mm),进样量:5 μL,柱温箱:30℃,流动相极性:正己烷/异丙醇=90/10,流速: 1.0毫升/分钟,紫外灯波长:254 nm,保留时间(多) = 6.47分钟, 保留时间(少) = 7.78分钟。
白色固体,产率91%,90% ee;[α]D19 = +54.1 (c = 1.2, CHCl3). 1H NMR (400MHz,d 6 -DMSO) δ 9.81 (s, 1H), 9.19 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.33 (d,J = 7.6 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 3.78 (q,J = 6.8 Hz, 1H), 2.43 (d, J = 7.2 Hz, 2H), 1.86-1.80 (m, 1H), 1.42 (d, J =6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 6H); 13C NMR (101 MHz, d 6 -DMSO) δ 171.6,153.2, 139.4, 139.3, 130.9, 128.8, 126.9, 120.8, 115.0, 45.4, 44.2, 29.6,22.2, 18.7. 高效液相测试条件:大赛璐手性IG柱(规格:4.6x250 mm),进样量:5 μL,柱温箱:30℃,流动相极性:正己烷/异丙醇=85/15,流速: 1.0毫升/分钟,紫外灯波长:254 nm,保留时间(少) = 10.66分钟, 保留时间(多) = 15.98分钟。
实施例5:向20.0毫升玻璃瓶中加入6-甲氧基-2-萘乙烯(1.2毫摩尔,1.2当量),苯胺(1.0毫摩尔,1.0当量),PdI2(0.01毫摩尔,1 mol%),L9(0.02毫摩尔,2 mol%)和乙二醇二甲醚(5.0毫升)。然后将玻璃瓶放入高压釜中,加压至50个大气压的CO。将高压釜中的反应混合物在室温下搅拌15天后,将高压釜中的CO小心地释放到通风良好的通风橱中。通过GC-MS分析粗产物确定支链酰胺:直链酰胺> 99:1。反应混合物通过柱色谱分离得到5q,洗脱剂:石油醚和乙酸乙酯(10:1,体积比);
白色固体,产率91%,90% ee;[α]D18 = +48.2 (c = 0.9, CHCl3). 1H NMR (400MHz, CDCl3) δ 7.71 (t, J = 10.2 Hz, 3H), 7.42-7.39 (m, 3H), 7.25-7.23 (m,3H), 7.18-7.15 (m, 1H), 7.13-7.11 (m, 1H), 7.04 (t, J = 7.2 Hz, 1H), 3.90 (s,3H), 3.83 (q, J = 7.2 Hz, 1H), 1.64 (d, J = 7.2 Hz, 3H); 13C NMR (101 MHz,CDCl3) δ 172.5, 157.8, 137.8, 136.0, 133.8, 129.2, 129.0, 128.8, 127.8,126.3, 126.1, 124.2, 119.7, 119.2, 105.6, 55.3, 47.9, 18.5. 高效液相测试条件:大赛璐手性IG柱(规格:4.6x250 mm),进样量:5 μL,柱温箱:30℃,流动相极性:正己烷/异丙醇=90/10,流速: 1.0毫升/分钟,紫外灯波长:254 nm,保留时间(多) = 17.46分钟, 保留时间(少) = 21.81分钟。
与化合物5q合成方法类似,仅改变底物可合成得到5r和5s化合物:
白色固体,产率83%,92% ee;[α]D19 = +29.6 (c = 1.4, CHCl3). 1H NMR (400MHz, d 6 -DMSO) δ 10.14 (s, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.54-7.52 (m, 2H),7.49-7.44 (m, 3H), 7.40-7.38 (m, 1H), 7.33-7.27 (m, 4H), 7.03 (t, J = 7.6 Hz,1H), 3.91 (q, J = 7.2 Hz, 1H), 1.46 (d, J = 7.2 Hz, 3H); 13C NMR (101 MHz, d 6 -DMSO) δ 171.7, 158.9 (d, J = 244.6 Hz), 143.7 (d, J = 7.6 Hz), 139.1, 134.9,130.7 (d, J = 3.5 Hz), 128.7, 128.6, 127.8, 126.6 (d, J = 13.3 Hz), 123.8,123.4, 119.2, 114.9 (d, J = 23.1 Hz), 45.5, 18.4. 高效液相测试条件:大赛璐手性IG柱(规格:4.6x250 mm),进样量:5 μL,柱温箱:30℃,流动相极性:正己烷/异丙醇=90/10,流速: 1.0毫升/分钟,紫外灯波长:254 nm,保留时间(多) = 8.42分钟, 保留时间(少) =10.95分钟。
白色固体,产率76%,93% ee;[α]D19 = +36.7 (c = 1.1, CHCl3). 1H NMR (400MHz, CDCl3) δ 7.84 (s, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.71-7.66 (m, 2H), 7.61(t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 6H), 7.29 (t, J = 8.8 Hz, 2H), 7.10(t, J = 7.2 Hz, 1H), 3.80 (q, J = 7.2 Hz, 1H), 1.62 (d, J = 6.8 Hz, 3H); 13CNMR (101 MHz, CDCl3) δ 196.6, 171.7, 141.5, 138.2, 137.8, 137.3, 132.6,131.4, 130.1, 129.3, 129.2, 128.9, 128.4, 124.4, 119.8, 47.9, 18.8. 高效液相测试条件:大赛璐手性IG柱(规格:4.6x250 mm),进样量:5 μL,柱温箱:30℃,流动相极性:正己烷/异丙醇=90/10,流速: 1.0毫升/分钟,紫外灯波长:254 nm,保留时间(多) = 17.41分钟, 保留时间(少) = 19.47分钟。
实施例6:
与实施例3-5合成方法类似,改变底物可得到不同产物。具体底物类型及产率和ee值数据见表2与表3,但底物范围不局限于表内,
上述得到的所有酰胺,均可以在硫酸水溶液中(浓度为1摩尔/升)水解后,以大于85%的产率得到相应的手性羧酸,ee值不发生改变。5p,5q,5r,5s,5t,5u水解后,得到手性非甾体抗炎药,见表4。
实施例7:本实施例与实施例3的不同之处仅在于:将(0.011毫摩尔,11mol%)的亚磷酰胺配体L9替换为表5中的任意配体(0.011毫摩尔,11mol%),其余内容均与实施例3所述相同。通过气质联用仪(GC-MS)分析粗产物得知,没有氢氨羰基化产物生成。
本发明中新开发的配体在钯催化不对称氢酯化反应中的应用
实施例8:向5.0毫升玻璃瓶中加入4-异丁基苯乙烯(0.2毫摩尔,1.0当量),甲醇(0.4毫摩尔,2.0当量),PdBr2(0.02毫摩尔,10mol%),L10(0.022毫摩尔,11mol%)和四氢呋喃(2.0毫升)。将玻璃瓶放入高压釜中加压至50个大气压的CO,之后在室温下搅拌72小时。将高压釜中的CO小心地释放到通风良好的通风橱中,取出反应,GC-MS分析粗产物确定支链酯:直链酯> 99:1。反应混合物通过柱色谱进行分离得6r,洗脱剂:石油醚和乙酸乙酯(10:1,体积比)。
无色液体,产率89%,92% ee;1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.0 Hz,2H), 7.12 (d, J = 8.0 Hz, 2H), 3.73 (q, J = 7.2 Hz, 1H), 3.68 (s, 3H), 2.47(d, J = 7.2 Hz, 2H), 1.92-1.82 (m, 1H), 1.51 (d, J = 7.2 Hz, 3H), 0.93 (d, J= 6.6 Hz, 6H). 高分辨质谱(ESI电离源),m/z C14H20O2: [M+Na] +的理论值:243.1356,实测值:243.1359. 高效液相测试条件:大赛璐手性IG柱(规格:4.6x250 mm),进样量:5 μL,柱温箱:30℃,流动相极性:正己烷/异丙醇=98/2,流速: 1.0毫升/分钟,紫外灯波长:220nm,保留时间(少) = 4.81分钟, 保留时间(多) = 5.09分钟。
实施例9:向20毫升玻璃瓶中加入6-甲氧基-2-萘乙烯(1.0毫摩尔,1.0当量),甲醇(2.0毫摩尔,2.0当量),PdI2(0.02毫摩尔,2 mol%),L11(0.03毫摩尔,3 mol%)和乙二醇二甲醚(10.0毫升)。将玻璃瓶放入高压釜中加压至50个大气压的CO,之后在室温下搅拌10天。将高压釜中的CO小心地释放到通风良好的通风橱中,取出反应,GC-MS分析粗产物确定支链酯:直链酯> 99:1。反应混合物通过柱色谱进行分离得6s,洗脱剂:石油醚和乙酸乙酯(100:1,体积比)。
白色固体,产率93%,91%ee;1H NMR (400 MHz, CDCl3) δ 7.74-7.61 (m, 3H),7.39 (dd, J = 8.4, 1.6 Hz, 1H), 7.17-7.02 (m, 2H), 3.87 (s, 3H), 3.84 (q, J =7.2 Hz, 1H), 3.65 (s, 3H), 1.57 (d, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)δ 175.0, 157.5, 135.6, 133.6, 129.2, 128.8, 127.1, 126.1, 125.8, 118.9,105.4, 55.1, 51.9, 45.2, 18.5. 高分辨质谱(ESI电离源),m/z C15H16NaO3: [M+Na]+的理论值:267.0992, 实测值:267.0990. 高效液相测试条件:大赛璐手性IA柱(规格:4.6x250 mm),进样量:5 μL,柱温箱:30℃,流动相极性:正己烷/异丙醇=98/2,流速: 0.7毫升/分钟,紫外灯波长:220 nm,保留时间(少) = 6.67分钟, 保留时间(多) = 7.92分钟。
实施例10:
与实施例8和9合成方法类似,改变底物可得到不同产物。具体底物类型及产率和ee值数据见表6与表7,但底物范围不局限于表内,
上述得到的所有酯,均可以在硫酸水溶液中(浓度为1摩尔/升)水解后,以大于85%的产率得到相应的手性酸,ee值不发生改变。(见表8)
实施例11:本实施例与实施例8的不同之处仅在于:将(0.022毫摩尔,11mol%)的亚磷酰胺配体L10替换为表5中的任意配体(0.022毫摩尔,11mol%),其余内容均与实施例8所述相同。通过气质联用仪(GC-MS)分析粗产物得知,没有氢酯化产物生成。
本发明中新开发的配体在氢羧基化反应中的应用
实施例12:向20毫升玻璃瓶中加入4-异丁基苯乙烯(1.0毫摩尔,1.0当量),水(2.0毫摩尔,2.0当量),PdBr2(0.05毫摩尔,5mol%),L5(0.06毫摩尔,6 mol%),HBr(0.1毫摩尔,10 mol%)和四氢呋喃(10.0毫升)。将玻璃瓶放入高压釜中加压至50个大气压的CO,之后在室温下搅拌反应5天。将高压釜中的CO小心地释放到通风良好的通风橱中,取出反应,GC-MS分析粗产物确定支链羧酸:直链羧酸> 99:1。反应混合物通过柱色谱进行分离得到布洛芬8r,洗脱剂:石油醚和乙酸乙酯(10:1,体积比),
白色固体,产率93%,92% ee;1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.0 Hz,2H), 7.09 (d, J = 8.0 Hz, 2H), 3.70 (q, J = 7.2 Hz, 1H), 2.44 (d, J = 7.2 Hz,2H), 1.87-1.81 (m, 1H), 1.49 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.8 Hz, 6H);13C NMR (101 MHz, CDCl3) δ 181.5, 140.8, 136.9, 129.4, 127.3, 45.02, 44.97,30.2, 22.4, 18.1. 高分辨质谱(ESI电离源),m/z C13H19O2: [M+H] +的理论值:207.1380,实测值:207.1386.8r与重氮甲烷反应生成6r后进行ee值测试。
实施例13:向20毫升玻璃瓶中加入6-甲氧基-2-萘乙烯(1.0毫摩尔,1.0当量),水(2.0毫摩尔,2.0当量),PdI2(0.1毫摩尔,10mol%),L20(0.11毫摩尔,11mol%),HI(0.2毫摩尔,20mol%)和四氢呋喃(10.0毫升)。将玻璃瓶放入高压釜中加压至50个大气压的CO,之后在室温下搅拌反应72小时。将高压釜中的CO小心地释放到通风良好的通风橱中,取出反应,GC-MS分析粗产物确定支链羧酸:直链羧酸> 99:1。反应混合物通过柱色谱进行分离得到萘普生8s,洗脱剂:石油醚和乙酸乙酯(10:1,体积比)。
白色固体,产率87%,88% ee;1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.67(s, 2H), 7.40 (dd, J = 8.8, 2.0 Hz, 1 H), 7.12 (dt, J = 8.8, 2.4 Hz, 1H),7.09 (d, J = 2.4 Hz, 1H), 3.89 (s, 3H), 3.85 (q, J = 7.2 Hz, 1H), 1.57 (d, J= 7.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 180.9, 157.6, 134.8, 133.8, 129.3,128.8, 127.2, 126.2, 126.1, 119.0, 105.5, 55.3, 45.2, 18.1. 高分辨质谱(ESI电离源),m/z C13H19O2: [M-H]-的理论值:229.0859, 实测值:229.0863. 8s与重氮甲烷反应生成6s后进行ee值测试。
实施例14:向20毫升玻璃瓶中加入3-氟-4-苯基苯乙烯(1.0毫摩尔,1.0当量),水(2.0毫摩尔,2.0当量),PdCl2(0.1毫摩尔,10 mol%),L14(0.11毫摩尔,11 mol%),HCl(0.2毫摩尔,20 mol%)和四氢呋喃(10.0毫升)。将玻璃瓶放入高压釜中加压至50个大气压的CO,之后在室温下搅拌反应72小时。将高压釜中的CO小心地释放到通风良好的通风橱中,取出反应,GC-MS分析粗产物确定支链羧酸:直链羧酸> 99:1。反应混合物通过柱色谱进行分离得到氟比洛芬8t,洗脱剂:石油醚和乙酸乙酯(10:1,体积比)。
白色固体,产率93%,91% ee;1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.52(d, J = 8.0 Hz, 2H), 7.44-7.35 (m, 4H), 7.19-7.14 (m, 2H), 3.76 (q, J = 7.2Hz, 1H), 1.54 (d, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 177.8, 159.6 (d,J = 249.2 Hz), 141.7 (d, J = 7.8 Hz), 135.5, 130.7 (d, J = 4.0 Hz), 128.9 (d,J = 2.9 Hz), 128.4, 127.8 (d, J = 13.5 Hz), 127.6, 123.6 (d, J = 3.3 Hz),115.3 (d, J = 23.7 Hz), 44.9, 18.1; 高分辨质谱(ESI电离源),m/z C15H12FO2: [M-H]-的理论值:243.0816, 实测值:243.0821. 8t与重氮甲烷反应生成6t后,进行ee值测试。
实施例15:与实施例12-14合成方法类似,改变底物可得到不同产物。具体底物类型及产率和ee值数据见表9,但底物范围不局限于表内,
实施例16:本实施例与实施例12的不同之处仅在于:将(0.11毫摩尔,11mol%)的亚磷酰胺配体L5替换为表5中的任意配体(0.11毫摩尔,11mol%),其余内容均与实施例12所述相同,通过气质联用仪(GC-MS)分析粗产物得知,没有氢羧基化产物的生成。
实施例17:本实施例与实施例14的不同之处仅在于:CO的压力为20个大气压时,产率为51%。
实施例18:本实施例与实施例14的不同之处仅在于:把四氢呋喃换成甲苯,产率为25%。
实施例19:本实施例与实施例14的不同之处仅在于:反应温度为80 oC,产率99%,75% ee。
最后有必要在此说明的是:上述实施例只用于对本发明的技术方案作进一步详细地说明,不能理解为对本发明保护范围的限制。本领域技术人员可以理解,根据本发明的上述内容,可对本发明做出一些修改或调整。这些修改或调整也应当在本发明权利要求所限定的范围之内。
Claims (10)
1.结构通式(I)和(II)所示的化合物,
R1选自C6~C24的芳基或取代芳基,所述取代芳基中的取代基为C1~C12的烷基、C1~C6的烷氧基、C1~C6的烷基氨基、卤素基、硝基、氰基、C1~C12的卤代烷基、C6~C18的芳基;
R2和R3独立地选自氢、C1~C6的烷基、C1~C6的卤代烷基、C1~C6的烷氧基、卤素基、C6~C18的芳基、硝基、氰基;
X选自氧、硫、
R4和R5独立地选自氢、C1-C6的烷基、C1-C6的烷氧基、C6~C12的芳基;
R6选自C1-C6的烷基、C6~C12的芳基或取代的芳基,所述取代芳基中的取代基为C1~C6的烷基、C1~C6的烷氧基、卤素基、硝基。
2.权利要求1所述化合物的制备方法,其特征在于包括以下步骤:
(a)将化合物A1或化合物A2,与芳基硼酸在钯催化下发生Suzuki偶联反应分别得到化合物B1或B2;
(b)将化合物C与三氯化磷反应得到化合物D;
(c)将化合物D与化合物B1或B2反应得到化合物(I)或(II);
3.权利要求1所述化合物在烯烃的不对称氢氨羰基化反应中的应用,
R7选自氢、C1-C16的烷基或取代烷基、C1-C16的烷氧基或取代烷氧基、C1-C6的酰氧基或取代酰氧基、C2-C12的烯基或炔基、C6~C16的芳基或取代的芳基、C3~C16的杂芳基或取代的杂芳基、二茂铁基或取代的二茂铁基、氨基、氰基,
所述的杂芳基为氮杂芳基、氧杂芳基、硫杂芳基,
所述取代烷基中的取代基、取代烷氧基中的取代基、取代酰氧基中的取代基、取代芳基中的取代基、取代杂芳基中的取代基和取代二茂铁基中的取代基为C1~C8的烷基、C1~C6的卤代烷基、C1~C6的烷氧基、C1~C6的酰氧基、C1~C6的酰氨基、C1~C6的烷基氨基、卤素基、硝基、羟基、氰基;
R8和R9独立地选自氢、C1-C16的烷基或取代烷基、C1~C16的卤代烷基、C2-C12的烯基或炔基、C6~C16的芳基或取代的芳基、C4~C16的杂芳基或取代的杂芳基、二茂铁基或取代的二茂铁基,
所述的杂芳基为氮杂芳基、氧杂芳基、硫杂芳基,
所述取代烷基中的取代基、取代芳基中的取代基、取代杂芳基中的取代基和取代二茂铁基中的取代基为C1~C6的烷基、C1~C6的卤代烷基、C1~C6的烷氧基、C1~C6的酰氧基、C1~C6的酰氨基、C1~C6的烷基氨基、卤素基、羟基、硝基、氰基。
4.权利要求1所述化合物在烯烃的不对称氢酯化或氢羧酸化反应中的应用,
R7选自氢、C1-C16的烷基或取代烷基、C1-C16的烷氧基或取代烷氧基、C1-C6的酰氧基或取代酰氧基、C2-C12的烯基或炔基、C6~C16的芳基或取代的芳基、C3~C16的杂芳基或取代的杂芳基、二茂铁基或取代的二茂铁基、氨基、氰基,
所述的杂芳基为氮杂芳基、氧杂芳基、硫杂芳基,
所述取代烷基中的取代基、取代烷氧基中的取代基、取代酰氧基中的取代基、取代芳基中的取代基、取代杂芳基中的取代基和取代二茂铁基中的取代基为C1~C8的烷基、C1~C6的卤代烷基、C1~C6的烷氧基、C1~C6的酰氧基、C1~C6的酰氨基、C1~C6的烷基氨基、卤素基、硝基、羟基、氰基;
R10独立地选自氢、C1-C16的烷基或取代烷基、C1~C16的卤代烷基、C6~C16的芳基或取代的芳基,
所述取代烷基中的取代基和取代芳基中的取代基为C1~C6的烷基、C1~C6的卤代烷基、C1~C6的烷氧基、C2-C6的烯基或炔基、C1~C6的酰氧基、C1~C6的酰氨基、C1~C6的烷基氨基、卤素基、硝基、氰基。
5.根据权利要求4所述的应用,其特征在于:反应体系加入了酸,酸的加入量为钯催化剂的1~5倍摩尔量,所述的酸为盐酸、硫酸、氢溴酸、氢碘酸、三氟乙酸、对甲苯磺酸、硼酸、特戊酸。
6.根据权利要求3或4所述的应用,其特征在于:所述的钯催化剂为Pd2(dba)3、Pd(dba)2、醋酸钯、三氟乙酸钯、氯化钯、溴化钯以及碘化钯。
7.根据权利要求3或4所述的应用,其特征在于:所述的一氧化碳压力为30~50个大气压。
8.根据权利要求3或4所述的应用,其特征在于:反应在有机溶剂中进行,所述的有机溶剂为乙醚、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、苯甲醚、乙二醇二甲醚、甲基叔丁基醚。
9.根据权利要求3所述的应用,其特征在于得到如下产物:
10.根据权利要求4所述的应用,其特征在于得到如下产物:
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