CN113185404A - 一种1,2-双轴手性联芳基化合物及其制备方法和应用 - Google Patents
一种1,2-双轴手性联芳基化合物及其制备方法和应用 Download PDFInfo
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- CN113185404A CN113185404A CN202110482565.8A CN202110482565A CN113185404A CN 113185404 A CN113185404 A CN 113185404A CN 202110482565 A CN202110482565 A CN 202110482565A CN 113185404 A CN113185404 A CN 113185404A
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- equal
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- chiral
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- -1 biaryl compound Chemical class 0.000 title claims abstract description 95
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 101
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000002808 molecular sieve Substances 0.000 claims abstract description 46
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 125000003118 aryl group Chemical group 0.000 claims abstract description 21
- 150000001503 aryl iodides Chemical class 0.000 claims abstract description 18
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 16
- 150000001499 aryl bromides Chemical class 0.000 claims abstract description 13
- 230000009471 action Effects 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 125000003518 norbornenyl group Chemical class C12(C=CC(CC1)C2)* 0.000 claims abstract 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 96
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 93
- 229910052786 argon Inorganic materials 0.000 claims description 84
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 54
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 49
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 48
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 43
- 125000001424 substituent group Chemical group 0.000 claims description 20
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 claims description 19
- 125000004185 ester group Chemical group 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000003172 aldehyde group Chemical group 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 229910052700 potassium Inorganic materials 0.000 claims description 14
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 125000003368 amide group Chemical group 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910021606 Palladium(II) iodide Inorganic materials 0.000 claims description 2
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000001348 alkyl chlorides Chemical class 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 150000001555 benzenes Chemical group 0.000 claims description 2
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 claims description 2
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical group C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- HNNUTDROYPGBMR-UHFFFAOYSA-L palladium(ii) iodide Chemical compound [Pd+2].[I-].[I-] HNNUTDROYPGBMR-UHFFFAOYSA-L 0.000 claims description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical group C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 2
- 125000005581 pyrene group Chemical group 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical group C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 7
- CISNNLXXANUBPI-UHFFFAOYSA-N cyano(nitro)azanide Chemical group [O-][N+](=O)[N-]C#N CISNNLXXANUBPI-UHFFFAOYSA-N 0.000 claims 1
- 239000003446 ligand Substances 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 174
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 164
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
- 150000001875 compounds Chemical class 0.000 description 79
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 63
- 239000000203 mixture Substances 0.000 description 60
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 41
- 238000004440 column chromatography Methods 0.000 description 41
- 239000002904 solvent Substances 0.000 description 41
- 238000004364 calculation method Methods 0.000 description 40
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 40
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 239000011259 mixed solution Substances 0.000 description 39
- VYHVHWVKRQHORF-RQJHMYQMSA-N methyl (1S,4R)-bicyclo[2.2.1]hept-2-ene-2-carboxylate Chemical compound COC(=O)C1=C[C@@H]2CC[C@H]1C2 VYHVHWVKRQHORF-RQJHMYQMSA-N 0.000 description 37
- 238000004128 high performance liquid chromatography Methods 0.000 description 34
- 238000003760 magnetic stirring Methods 0.000 description 33
- NHPPIJMARIVBGU-UHFFFAOYSA-N 1-iodonaphthalene Chemical compound C1=CC=C2C(I)=CC=CC2=C1 NHPPIJMARIVBGU-UHFFFAOYSA-N 0.000 description 28
- QAOFGUXVDAZKBW-UHFFFAOYSA-N methyl 2-bromo-3-methylbenzoate Chemical compound COC(=O)C1=CC=CC(C)=C1Br QAOFGUXVDAZKBW-UHFFFAOYSA-N 0.000 description 28
- 238000004821 distillation Methods 0.000 description 27
- 239000007787 solid Substances 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 22
- 239000007788 liquid Substances 0.000 description 18
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 14
- 239000007795 chemical reaction product Substances 0.000 description 14
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 14
- 239000011591 potassium Substances 0.000 description 12
- 150000002848 norbornenes Chemical class 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 10
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 7
- 238000012216 screening Methods 0.000 description 7
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
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- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
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- 238000004679 31P NMR spectroscopy Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
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- QAUOJYDYLGGPJN-UHFFFAOYSA-N (2-bromo-3-methylphenyl)-pyrrolidin-1-ylmethanone Chemical compound CC1=CC=CC(C(=O)N2CCCC2)=C1Br QAUOJYDYLGGPJN-UHFFFAOYSA-N 0.000 description 1
- OEHHXVIJMCMYGM-UHFFFAOYSA-N 1-chloro-3-iodo-2-methylbenzene Chemical compound CC1=C(Cl)C=CC=C1I OEHHXVIJMCMYGM-UHFFFAOYSA-N 0.000 description 1
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- DANMWBNOPFBJSZ-UHFFFAOYSA-N 1-iodo-2,3-dimethylbenzene Chemical group CC1=CC=CC(I)=C1C DANMWBNOPFBJSZ-UHFFFAOYSA-N 0.000 description 1
- ARJHCXYRCLMLQN-UHFFFAOYSA-N 1-iodo-2-methyl-4-nitrobenzene Chemical compound CC1=CC([N+]([O-])=O)=CC=C1I ARJHCXYRCLMLQN-UHFFFAOYSA-N 0.000 description 1
- RINOYHWVBUKAQE-UHFFFAOYSA-N 1-iodo-2-methylbenzene Chemical compound CC1=CC=CC=C1I RINOYHWVBUKAQE-UHFFFAOYSA-N 0.000 description 1
- SORQIYFSJAWBNQ-UHFFFAOYSA-N 1-iodo-2-propan-2-ylbenzene Chemical compound CC(C)C1=CC=CC=C1I SORQIYFSJAWBNQ-UHFFFAOYSA-N 0.000 description 1
- CWNJSSNWLUIMDP-UHFFFAOYSA-N 1-iodopyrene Chemical compound C1=C2C(I)=CC=C(C=C3)C2=C2C3=CC=CC2=C1 CWNJSSNWLUIMDP-UHFFFAOYSA-N 0.000 description 1
- GCAAVRIWNMTOKB-UHFFFAOYSA-N 2-bromo-1-methyl-3-nitrobenzene Chemical compound CC1=CC=CC([N+]([O-])=O)=C1Br GCAAVRIWNMTOKB-UHFFFAOYSA-N 0.000 description 1
- UCZAIRKLYNJMKO-UHFFFAOYSA-N 2-bromo-N,N,3-trimethylbenzamide Chemical compound CN(C)C(=O)c1cccc(C)c1Br UCZAIRKLYNJMKO-UHFFFAOYSA-N 0.000 description 1
- RZGYAMQMAVTAKP-UHFFFAOYSA-N 4-fluoro-2-iodo-1-methylbenzene Chemical compound CC1=CC=C(F)C=C1I RZGYAMQMAVTAKP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- XUFQHGKJPPCWQR-UHFFFAOYSA-N CC1=CC=CC(C(=O)OC(C)(C)C)=C1Br Chemical compound CC1=CC=CC(C(=O)OC(C)(C)C)=C1Br XUFQHGKJPPCWQR-UHFFFAOYSA-N 0.000 description 1
- ZGPRALXCTCVRCZ-UHFFFAOYSA-N COC(=O)c1cc(C)cc(C)c1Br Chemical compound COC(=O)c1cc(C)cc(C)c1Br ZGPRALXCTCVRCZ-UHFFFAOYSA-N 0.000 description 1
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- 125000005605 benzo group Chemical group 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000005841 biaryl group Chemical group 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical class FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 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
- DAUCSGSCDZOKLE-UHFFFAOYSA-N methyl 1-bromonaphthalene-2-carboxylate Chemical compound C1=CC=CC2=C(Br)C(C(=O)OC)=CC=C21 DAUCSGSCDZOKLE-UHFFFAOYSA-N 0.000 description 1
- YNHWTTUTWBNFGQ-UHFFFAOYSA-N methyl 2-(2-iodophenyl)acetate Chemical compound COC(=O)CC1=CC=CC=C1I YNHWTTUTWBNFGQ-UHFFFAOYSA-N 0.000 description 1
- DNUFRSWMGHFSJQ-UHFFFAOYSA-N methyl 2-bromo-3,4-dimethylbenzoate Chemical compound COC(=O)c1ccc(C)c(C)c1Br DNUFRSWMGHFSJQ-UHFFFAOYSA-N 0.000 description 1
- WDWUNVWWBHXXDL-UHFFFAOYSA-N methyl 2-bromo-3-ethylbenzoate Chemical compound BrC1=C(C(=O)OC)C=CC=C1CC WDWUNVWWBHXXDL-UHFFFAOYSA-N 0.000 description 1
- GPCKXHLBDYPOJR-UHFFFAOYSA-N methyl 2-bromo-5-chloro-3-methylbenzoate Chemical compound COC(=O)c1cc(Cl)cc(C)c1Br GPCKXHLBDYPOJR-UHFFFAOYSA-N 0.000 description 1
- IPPPZCXGKFWQEC-UHFFFAOYSA-N methyl 3-iodo-2-methylbenzoate Chemical compound COC(=O)C1=CC=CC(I)=C1C IPPPZCXGKFWQEC-UHFFFAOYSA-N 0.000 description 1
- HCSGWQGKCVQIRM-UHFFFAOYSA-N methyl 4-iodo-3-methylbenzoate Chemical compound COC(=O)C1=CC=C(I)C(C)=C1 HCSGWQGKCVQIRM-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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Abstract
本发明公开了一种1,2‑双轴手性联芳基化合物及其制备方法和应用。在气体保护下,不对称芳基碘化物、不对称芳基溴化物、不对称芳基或杂芳基三氟硼酸盐在钯催化剂、手性降冰片烯衍生物、碱以及
Description
技术领域
本发明涉及一种1,2-双轴手性联芳基化合物及其制备方法和应用,属于有机合成领域。
背景技术
轴手性联芳基骨架是一类非常重要的结构单元,广泛存在于具有生物活性的天然产物、药物分子以及手性材料中([1]Q.Li,L.Green,N.Venkataraman,I.Shiyanovskaya,A.Khan,A.Urbas,J.W.Doane,J.Am.Chem.SOC.2007,129,12908;[2]J.E.Smyth,N.M.Butler,P.A.Keller,Nat.Prod.Rep.2015,32,1562;[3]J.Clayden,W.J.Moran,P.J.Edwards,S.R.LaPlante,Angew.Chem.Int.Ed.2009,48,6398)。此外,以轴手性联芳基为骨架的手性配体和催化剂在不对称催化反应中具有重要作用([1]R.Noyori,H.Takaya,Acc.Chem.Res.1990,23,345;[2]Y.Chen,S.Yekta,A.K.Yudin,Chem.Rev.2003,103,3155;[3]D.Parmar,E:Sugiono,S..Raja,M.Rueping,Chem.Rev.2014,114,9047)。鉴于此类结构骨架的重要性,化学家发展了诸多合成方法。然而,这些方法大多都是合成单轴手性联芳基骨架,对于多轴手性联芳基骨架报道的例子很少,其中1,2-双轴手性联芳基化合物的合成报道则更少。极大地限制了1,2-双轴手性联芳基化合物的使用范围。因此发展高效、简洁的合成新方法显得尤为重要。
发明内容
为了解决现有技术中存在的不足,本发明提供一种1,2-双轴手性联芳基化合物及其制备方法和应用。该方法所用的原料廉价易得,反应条件温和,底物普适性好,产率高,制备过程简单。本发明以易得的不对称芳基碘化物A、不对称芳基溴化物B、不对称三氟硼酸有机盐C为起始原料,在钯催化剂、手性降冰片烯衍生物、碱以及分子筛的作用下,于110~130℃下的有机溶剂中搅拌反应,即可得1,2-双轴手性联芳基化合物。该1,2-双轴手性联芳基化合物可应用于新型手性配体及手性催化剂的合成。
本发明提供的技术方案具体如下:
第一方面,本发明提供一种1,2-双轴手性联芳基化合物,具有通式I所示的结构:
其中:
R1~R7分别独立地选自芳基、杂芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、膦基、苄氧基、烯基、炔基、Cl、F中的一种,且R2、R3不相同;或
R4、R7独立地为Br;或
(i)R1与1~3个R4之间、(ii)R3与2~3个R5之间、(iii)R6与1~3个R7之间可互相连接形成环状结构Ar1,Ar1为取代或未取代的苯环、杂环芳环、萘环、菲环、芘环、吡啶环、吲哚环、二苯并呋喃环、苯并噻吩环、喹啉环中的一种,Ar1上的取代基为芳基、杂芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、膦基、苄氧基、烯基、炔基、Cl、F中的一种或多种;
L代表O、S、N、C=C、C=O、C=S、C=N中的一种;
m表示R4的个数,0≤m≤3;当m≥2时,多个R4基团相同或不同;
n表示R5的个数,0≤n≤3;当n≥2时,多个R5基团相同或不同;
p表示R7的个数,0≤p≤3;当p≥2时,多个R7基团相同或不同。
第二方面,本发明提供一种1,2-双轴手性联芳基化合物的制备方法,包括以下步骤:气体保护下,不对称芳基碘化物A、不对称芳基溴化物B、不对称三氟硼酸有机盐C在钯催化剂、手性降冰片烯衍生物、碱以及分子筛的作用下于有机溶剂中反应,得到如通式I所示结构的1,2-双轴手性联芳基化合物;
其中,M选自K、Na、Li中的一种;R1~R7、L、m、n、p如前所述。
作为上述技术方案的优选,当R1与1~3个R4之间互相连接形成环状结构Ar1时,不对称芳基碘化物A的结构式为
R4、R4b、R4c、R4d分别独立地选自芳基、杂芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、膦基、苄氧基、烯基、炔基、Cl、F中的一种;
m1代表R4的个数,0≤m1≤2;当m1≥2时,多个R4基团相同或不同;
m2表示R4a的个数,0≤m2≤3;当m2≥2时,多个R4a基团相同或不同;
m3表示R4b的个数,0≤m3≤3;当m3≥2时,多个R4b基团相同或不同;
m4表示R4c的个数,0≤m4≤3;当m4≥2时,多个R4c基团相同或不同。
作为上述技术方案的优选,R2为吸电子基,选自酯基、醛基、羧基、氰基、硝基、磺酰基、膦基中的一种,R3为给电子基。
作为上述技术方案的优选,当R3与2~3个R5之间互相连接形成环状结构Ar1时,不对称芳基溴化物B的结构式为R2为吸电子基,选自酯基、醛基、羧基、氰基、硝基、磺酰基、膦基中的一种,L代表O、S、N、C=C、C=O、C=S、C=N中的一种,Ar1为五元环或六元环。
作为上述技术方案的优选,当R6与1~3个R7之间互相连接形成环状结构Ar1时,不对称三氟硼酸有机盐C的结构式为
R7、R7a、R7b、R7c分别独立地选自芳基、杂芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、膦基、苄氧基、烯基、炔基、Cl、F、Br中的一种;
p1代表R7的个数,0≤p1≤3;当p1≥2时,多个R7基团相同或不同;
p2代表R7a的个数,0≤p2≤4;当p2≥2时,多个R7a基团相同或不同;
p3代表R7b的个数,0≤p3≤4;当p3≥2时,多个R7b基团相同或不同;
p4代表R7c的个数,0≤p4≤4;当p4≥2时,多个R7c基团相同或不同。
作为上述技术方案的优选,手性降冰片烯衍生物的结构式为:
其中:
i)R8为左边五元环上的取代基,q代表取代基个数,0≤q≤8;R9为双键上的取代基,r代表取代基个数,0≤r≤2;
ii)R8,R9选自芳基、杂芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、烯基、炔基或卤素中的任意一种或几种;
iii)左边五元环上取代基数目为2个及2个以上时,可以相同,也可以不相同;双键上的取代基数目为2个时,可以相同,也可以不相同;
iv)R8和R9取代基的种类可以相同,也可以不相同。
作为上述技术方案的优选,钯催化剂选自Pd(PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、PdI2、[Pd(allyl)Cl]2中的任意一种或几种;碱选自碳酸钠、碳酸钾、碳酸铯、醋酸钠、醋酸钾、醋酸铯、磷酸三钾、甲酸钾、氢氧化钠、叔丁醇钠中的任意一种或几种;有机溶剂选自甲醇、乙醇、异丙醇、叔丁醇、四氢呋喃、2-甲基四氢呋喃、乙醚、二甲基乙二醚、甲基叔丁基醚、1,4-二氧六烷、1,3-二氧六烷、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、C4-12的饱和烷烃、C3-12的氟代或者氯代烷烃、苯、甲苯、二甲苯、三甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、N-甲基吡咯烷酮、乙腈、C3-12的饱和烷基腈中的任意一种或几种。
反应时间为1~48小时,反应温度为110~130℃。加热过程可采用油浴(如硅油、石蜡油等)或者其它加热方式。反应温度优选为105~110℃,更优选为110℃。
作为上述技术方案的优选,钯催化剂为醋酸钯,反应温度为110℃,碱为碳酸钾,溶剂为乙腈。
本发明优选在反应完成后对反应产物进行后处理,包括抽滤、浓缩和纯化。抽滤过程可使用砂芯漏斗在减压的条件下过滤。浓缩过程可采用减压蒸馏等方法,例如用旋转蒸发仪减压浓缩。纯化方法可采用柱层析分离纯化。
本发明提供的技术方案具有以下有益效果:
1、本发明所涉及的主要原料为不对称芳基碘化物、不对称芳基溴化物、不对称芳基或杂芳基三氟硼酸钾盐,此原料可用商品化试剂,无需特殊处理,且价格低廉,种类繁多。
2、本发明方法具有非常好的对映选择性和非对映选择性,所得产物的ee值高达99%,dr值高达20∶1。
3、本发明方法所涉及的反应使用的催化剂是较为廉价的金属钯盐,相比于其他催化剂或者络合物等是一个重要的补充;
4、本发明方法所涉及的反应使用的催化量的降冰片烯衍生物,相比于之前的反应使用的降冰片烯的用量大大减少;
5、本发明方法所涉及的反应对官能团具有很好的容忍性和普适性,取代基可以为烷基、烷氧基、酯基、硝基、卤原子(F、Cl、Br)等。
6、本发明方法可以高效、大量(克级)地制备1,2-双轴手性联芳基化合物,为工业化生产奠定了良好的基础。
具体实施方式
下面通过实施例对本发明的技术方案给予进一步说明,值得注意的是,本发明的技术方案不仅限于以下实施例。
本发明首先对反应温度、不对称三氟硼酸有机盐、碱、钯催化剂、添加剂、手性降冰片烯衍生物、膦配体等重要因素进行筛选,结果如下:
1.反应温度选择:
如式①所示,氩气保护下,1.0当量不对称芳基碘化物1a、1.5当量不对称芳基溴化物2a、2.0当量不对称三氟硼酸有机盐3a-1在10mol%钯催化剂Pd(OAc)2、50mol%手性降冰片烯衍生物(±)-N1、2.5当量K2CO3的作用下于不同温度的四氢呋喃(0.2M,按每0.2mmol不对称芳基碘化物1a加入1mL四氢呋喃计)中反应,得到如4aaa所示结构的1,2-双轴手性联芳基化合物;反应温度与产率的关系如表1所示。
表1.反应温度的筛选
a表示所有反应中芳香碘化物1a的添加量为0.1mmol。b表示产率通过以联苯为内标的气相色谱测定。
表1实验结果表明,温度为90℃时仅有微量产物,温度超过110℃时产率反而降低,因此,温度应控制在105~110℃。
2.不对称三氟硼酸有机盐的筛选实验
如式②所示,氩气保护下,1.0当量不对称芳基碘化物1a、1.5当量不对称芳基溴化物2a与2.0当量不同种类的不对称三氟硼酸有机盐在10mol%钯催化剂Pd(OAc)2、50mol%手性降冰片烯衍生物(±)-N1、2.5当量K2CO3的作用下于110℃的四氢呋喃(0.2M,按每0.2mmol不对称芳基碘化物1a加入1mL四氢呋喃计)中反应24h,得到如4aaa所示结构的1,2-双轴手性联芳基化合物;不对称三氟硼酸有机盐种类与1,2-双轴手性联芳基化合物产率的关系如表2所示。
表2.不对称三氟硼酸有机盐的筛选
a表示所有反应中芳香碘化物1a的添加量为0.1mmol。b表示产率通过以联苯为内标的气相色谱测定。
表2中的实验结果表明,当选择3a作为不对称三氟硼酸有机盐时,1,2-双轴手性联芳基化合物的产率最高。因此,后续实验采用3a作为不对称三氟硼酸有机盐。
3.碱的筛选实验
如式③所示,氩气保护下,1.0当量不对称芳基碘化物1a、1.5当量不对称芳基溴化物2a与2.0当量不对称三氟硼酸有机盐3a在10mol%钯催化剂Pd(OAc)2、50mol%手性降冰片烯衍生物(±)-N1、2.5当量不同种类碱的作用下于110℃的四氢呋喃中(0.2M,按每0.2mmol不对称芳基碘化物1a加入1mL四氢呋喃计)反应24h,得到如4aaa所示结构的1,2-双轴手性联芳基化合物;碱的种类与1,2-双轴手性联芳基化合物产率的关系如表3所示。
表3.碱的种类与产率的关系
a表示所有反应中芳香碘化物1a的添加量为0.1mmol。b表示产率通过以联苯为内标的气相色谱测定。
表3实验结果表明,当选择K2CO3作为碱时,1,2-双轴手性联芳基化合物的产率最高。因此,后续实验采用K2CO3作为碱。
4.钯催化剂、添加剂、[NBE]的筛选实验
如式④所示,氩气保护下,1.0当量不对称芳基碘化物1a、1.5当量不对称芳基溴化物2a与2.0当量不对称三氟硼酸有机盐3a在10mol%不同种类的钯催化剂(简称[Pd])、50mol%不同种类的手性降冰片烯衍生物(简称[NBE])、2.5当量K2CO3的作用下于110℃的四氢呋喃(0.2M,按每0.2mmol不对称芳基碘化物1a加入1mL四氢呋喃计)中反应24h,得到如4aaa所示结构的1,2-双轴手性联芳基化合物;钯催化剂、手性降冰片烯衍生物的种类与1,2-双轴手性联芳基化合物产率、d.r.值、e.e.值的关系如表4所示。
表4钯催化剂、添加剂、[NBE]的筛选
a表示所有反应中芳香碘化物1a的添加量为0.1mmol。b表示产率通过以联苯为内标的气相色谱测定。c表示括号内为分离收率,d表示d.r.值通过1H NMR分析测定,e表示e.e.值通过手性HPLC分析测定。
表4所示的实验结果表明,未添加分子筛(简称MS)时,Pd(OAc)2、(±)-N1*催化下,4aaa产率为67%,添加分子筛后,4aaa产率提升至90%,d.r.值可达8.3∶1,e.e.值为99/99。
5.膦配体的筛选实验
如式⑤所示,氩气保护下,1.0当量不对称芳基碘化物1a、1.5当量不对称芳基溴化物2a与2.0当量不对称三氟硼酸有机盐3a在10mol%钯催化剂Pd(OAc)2、22mol%不同种类的膦配体、50mol%手性降冰片烯衍生物(±)-N2、2.5当量K2CO3的作用下于110℃的四氢呋喃(0.2M,按每0.2mmol不对称芳基碘化物1a加入1mL四氢呋喃计)中反应24h,得到如4aaa所示结构的1,2-双轴手性联芳基化合物;膦配体种类与1,2-双轴手性联芳基化合物产率、d.r.值的关系如表5所示。
表5膦配体与产率、d.r.值的关系
a表示所有反应中芳香碘化物1a的添加量为0.1mmol。b1表示产率通过以1,3,5-三甲氧基苯为内标的H NMR测定。d表示d.r.值通过1H NMR分析确定。
表5所示的实验结果表明,未添加膦配体时,1,2-双轴手性联芳基化合物的产率、d.r.值反而远高于添加膦配体时,因此,以下实施例中均不添加膦配体。
实施例1:化合物I-1的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-1(黄色油状液体,产率=88%,d.r=8.3∶1,主要非对映异构体e.e.>99%,次要非对映异构体e.e.>99%)。1HNMR(400MHz,CDCl3)(主要非对映异构体):δ8.06(d,J=8.5Hz,1H),7.99(d,J=8.5Hz,1H),7.80(d,J=8.2Hz,1H),7.70(d,J=8.2Hz,1H),7.58(d,J=8.4Hz,1H),7.49-7.45(m,1H),7.40-7.35(m,1H),7.31(d,J=7.7Hz,2H),7.25-7.19(m,4H),7.15(d,J=7.7Hz,1H),7.09-6.99(m,2H),3.27(s,3H),2.22(s,3H);13C NMR(100MHz,CDCl3)(主要非对映异构体):δ167.2,142.3,138.4,137.6,136.4,134.7,133.43,133.40,133.3,132.9,132.7,129.8,128.7,128.23,128.17,127.73,127.67,127.6,127.4,127.2,126.81,126.77,126.1,125.6,125.4,125.3,125.0,51.4,21.3;HRMS(ESI-TOF):理论计算值:C29H22NaO2 +[M+Na+]425.1512,实测值:425.1508;HPLC条件:Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=254nm,主要非对映异构体tR(major)=10.940min,次要非对映异构体tR(major)=6.919min。“
实施例2:化合物I-2的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、邻碘甲苯(21.8mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-2(白色固体,产率=50%,d.r.>20∶1,e.e.>99%)。1H NMR(400MHz,CDCl3):δ7.74(d,J=8.4Hz,1H),7.59(d,J=8.3Hz,1H),7.49-7.41(m,2H),7.40-7.31(m,3H),7.28-7.23(m,3H),7.13(t,J=7.7Hz,1H),6.98(t,J=7.6Hz,1H),6.88(d,J=7.0Hz,1H),3.28(s,3H),2.21(s,3H),1.94(s,3H);13C NMR(100MHz,CDCl3):δ167.0,142.5,140.6,137.72,137.69,137.53,137.45,133.3,131.8,129.5,128.7,128.3,127.9,127.6,127.2,127.1,127.0,126.5,125.7,125.4,125.3,124.9,51.4,21.4,20.8;HRMS(ESI-TOF):理论计算值:C26H22NaO2 +[M+Na+]389.1512,实测值:389.1505;HPLC条件:Daicel Chiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=230nm,tR(major)=5.327min。
实施例3:化合物I-3的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、2-乙基碘苯(23.2mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-3(白色固体,产率=53%,d.r.>20∶1,e.e.=99%)。1H NMR(400MHz,CDCl3):δ7.74(d,J=8.0Hz,1H),7.58(d,J=8.2Hz,1H),7.50(t,J=7.6Hz,1H),7.46-7.29(m,4H),7.24(d,J=7.9Hz,3H),7.13(t,J=7.6Hz,1H),6.96(t,J=7.7Hz,1H),6.92(d,J=7.0Hz,1H),3.30(s,3H),2.35-2.25(m,1H),2.24-2.11(m,4H),0.99(d,J=7.5Hz,3H);13C NMR(100MHz,CDCl3):δ167.0,143.4,142.7,140.6,137.7,137.4,136.8,133.3,133.2,132.2,129.4,128.2,127.8,127.6,127.3,127.2,127.1,126.8,126.5,126.1,125.33,125.27,124.8,51.4,26.8,21.4,15.4;HRMS(ESI-TOF):理论计算值:C27H24NaO2 +[M+Na+]403.1669,实测值:403.1662;HPLC条件:Daicel Chiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=220nm,rR(major)=4.892min,rR(minor)=4.585min。
实施例4:化合物I-4的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、2-异丙基碘苯(24.6mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-4(白色固体,产率=46%,d.r.>20∶1,e.e.=98%)。1H NMR(400MHz,CDCl3):δ7.77-7.72(m,1H),7.60-7.43(m,4H),7.40-7.31(m,2H),7.25-7.22(m,3H),7.13(dd,J=8.3,7.0Hz,1H),6.99-6.91(m,2H),3.31(s,3H),2.47-2.40(m,1H),2.19(s,3H),1.15(d,J=6.9Hz,3H),0.95(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ67.0,148.3,142.9,140.5,137.7,137.5,136.0,133.3,133.1,132.6,129.3,128.1,127.7,127.52,127.50,127.2,127.1,126.4,126.1,125.4,125.2,124.8,124.1,51.4,30.6,25.9,22.8,21.4;HRMS(ESI-TOF):理论计算值:C28H26NaO2 +[M+Na+]417.1825,实测值:417.1816;HPLC条件:Daicel Chiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=220nm,tR(major)=4.543min,tR(minor)=4.291min。
实施例5:化合物I-5的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、2-(2-碘苯基)乙酸甲酯(27.6mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-5(无色油状液体,产率=45%,d.r.>20∶1,e.e.>99%)。1H NMR(400MHz,CDCl3):δ7.74(d,J=7.5Hz,1H),7.60(d,J=8.2Hz,1H),7.53(t,J=7.6Hz,1H),7.44(d,J=7.7Hz,1H),7.41-7.29(m,4H),7.28-7.23(m,2H),7.13(dd,J=8.2,7.0Hz,1H),6.98(d,J=7.7Hz,1H),6.92(d,J=7.6Hz,1H),3.42(s,3H),3.33(d,J=16.2Hz,1H),3.32(s,3H),3.21(d,J=16.2Hz,1H),2.20(s,3H);13C NMR(100MHz,CDCl3):δ172.3,167.0,142.1,141.1,137.8,137.7,136.3,134.0,133.4,133.3,131.9,129.5,129.3,128.9,128.3,127.7,127.6,127.5,126.7,126.6,126.5,125.6,125.5,124.8,51.7,51.4,39.5,21.4;HRMS(ESI-TOF):理论计算值:C28H24NaO4 +[M+Na+]447.1567,实测值:447.1562;HPLC条件:Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=220nm,tR(major)=9.485min。
实施例6:化合物I-6的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘-2,3-二甲苯(23.2mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-6(白色固体,产率=63%,>d.r.=20∶1,e.e.=99%)。1H NMR(400MHz,CDCl3):δ7.75(d,J=7.5Hz,1H),7.58(d,J=8.2Hz,1H),7.45-7.40(m,1H),7.40-7.30(m,3H),7.28-7.19(m,2H),7.19-7.08(m,2H),6.96(t,J=7.6Hz,1H),6.87(dd,J=7.1,1.3Hz,1H),3.24(s,3H),2.42(s,3H),2.22(s,3H),1.83(s,3H);13C NMR(100MHz,CDCl3):δ167.0,143.0,138.3,138.2,137.8,137.3,135.9,135.4,133.23,133.21,132.2,129.6,128.8,128.2,127.5,127.4,127.2,127.1,126.3,125.9,125.32,125.26,124.9,51.3,21.4,20.9,17.5;HRMS(ESI-TOF):理论计算值:C27H24NaO2 +[M+Na+]403.1669,实测值:403.1661;HPLC条件:DaicelChiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=220nm,tR(maior)=6.269min,tR(minor)=4.865min。
实施例7:化合物I-7的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-氟-3-碘-2-甲基苯(23.6mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-7(白色固体,产率=50%,d.r.>20∶1,e.e.=99%)。1H NMR(400MHz,CDCl3):δ7.76(d,J=7.9Hz,1H),7.61(d,J=8.3Hz,1H),7.46-7.33(m,3H),7.30-7.21(m,4H),7.13(t,J=7.7Hz,1H),6.99(t,J=7.7Hz,1H),6.86(d,J=7.0Hz,1H),3.28(s,3H),2.21(s,3H),1.85(s,3H);13CNMR(100MHz,CDCl3):δ167.0,160.5(d,J=243.9Hz),141.8,139.7(d,J=4.4Hz),137.9,136.5(d,J=2.3Hz),136.3(d,J=3.6Hz),133.4,133.3,131.8,129.7,128.8,128.7,128.3,127.7,126.7,125.8,125.7,125.5,124.9,124.7(d,J=16.1Hz),114.0(d,J=23.0Hz),51.4,21.3,12.6(d,J=4.6Hz);19F NMR(376MHz,CDCl3):δ-117.7;HRMS(ESI-TOF):理论计算值:C26H21FNaO2 +[M+Na+]407.1418,实测值:407.1409;HPLC条件:DaicelChiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=210nm,tR(major)=5.935min,tR(minor)=4.818min。
实施例8:化合物I-8的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-氯-3-碘-2-甲基苯(25.3mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-8(无色油状液体,产率=38%,d.r.>20∶1,e.e.=99%)。1H NMR(400MHz,CDCl3)∶δ7.75(d,J=8.4Hz,1H),7.60(d,J=8.3Hz,1H),7.56(d,J=8.3Hz,1H),7.43-7.33(m,3H),7.29-7.17(m,3H),7.12(t,J=7.7Hz,1H),6.99(t,J=7.7Hz,1H),6.86(d,J=7.1Hz,1H),3.27(s,3H),2.21(s,3H),1.97(s,3H);
13C NMR(100MHz,CDCl3):δ166.9,141.7,139.4,139.3,137.6,137.1,135.7,133.7,133.4,133.3,131.8,129.4,128.8,128.3,128.1,127.7,126.81,126.76,125.73,125.68,125.5,124.9,51.4,21.3,18.4;HRMS(ESI-TOF):理论计算值:C26H21ClNaO2 +[M+Na+]423.1122,实测值:423.1121;HPLC条件:Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=220nm,rR(major)=8.396min,rR(minor)=4.749min。
实施例9:化合物I-9的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、3-碘-2-甲基苯甲酸甲酯(27.6mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-9(黄色油状液体,50%产率,d.r.=6.7∶1,主要非对映异构体>99%e.e.,次要非对映异构体>99%e.e.)。1H NMR (400MHz,CDCl3)(主要非对映异构体):δ8.05(d,J=8.1Hz,1H),7.75(d,J=7.6Hz,1H),7.60(d,J=8.3Hz,1H),7.42-7.30(m,4H),7.29-7.22(m,2H),7.12(t,J=7.6Hz,1H),7.00(t,J=7.7Hz,1H),6.87(d,J=7.2Hz,1H),3.95(s,3H),3.27(s,3H),2.19(s,3H),2.16(s,3H);13C NMR(100MHz,CDCl3)(主要非对映异构体):δ168.9,166.8,144.8,141.9,139.4,139.2,137.2,137.1,133.5,133.3,131.9,129.6,129.2,129.0,128.3,127.71,127.68,127.6,126.88,126.85,125.8,125.6,125.5,124.9,52.1,51.4,21.3,18.8;HRMS(ESI-TOF):理论计算值:C28H24NaO4 +[M+Na+]447.1567,实测值:447.1563;HPLC条件:Daicel Chiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=254nm,主要非对映异构体rR(major)=8.972min,次要非对映异构体rR(major)=7.568min。
实施例10:化合物I-10的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、4-碘-3-甲基苯甲酸甲酯(27.6mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-10(黄色油状液体,产率=59%,d.r.=7∶1,主要非对映异构体e.e.=99%,次要非对映异构体e.e.>99%)。1H NMR(400MHz,CDCl3)(主要非对映异构体):δ8.04(s,1H),7.95(s,1H),7.78-7.73(m,1H),7.65-7.60(d,J=8.3Hz,1H),7.43-7.31(m,3H),7.30-7.19(m,2H),7.18-7.12(m,1H),7.04-6.93(m,1H),6.87(d,J=7.1Hz,1H),3.94(s,3H),3.28(s,3H),2.20(s,3H),1.99(s,3H);13C NMR(100MHz,CDCl3)(主要非对映异构体):δ167.4,166.8,142.5,141.6,141.1,138.2,137.6,136.8,133.5,133.3,131.3,129.7,129.24,129.17,128.9,128.4,127.75,127.72,126.9,126.7,125.64,125.55,125.3,124.9,52.2,51.4,21.4,20.8;HRMS(ESI-TOF):理论计算值:C28H24NaO4 +[M+Na+]447.1567,实测值:447.1558;HPLC条件:Daicel Chiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=230nm,主要非对映异构体tR(major)=8.374min,rR(minor)=7.792min,次要非对映异构体rR(maior)=6.717min(minor)。
实施例11:化合物I-11的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘-2-甲基-4-硝基苯(26.3mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-11(黄色固体,产率=33%,d.r.=6.7∶1,主要非对映异构体e.e.=99%,次要非对映异构体e.e.>99%)。1H NMR (400MHz,CDCl3)(主要非对映异构体):δ8.26-8.21(m,1H),8.15(dd,J=2.4,0.7Hz,1H),7.79-7.76(m,1H),7.67-7.64(m,1H),7.45-7.35(m,3H),7.34-7.30(m,2H),7.17(dd,J=8.2,7.1Hz,1H),7.05(t,J=7.7Hz,1H),6.87(dd,J=7.1,1.2Hz,1H),3.31(s,3H),2.22(s,3H),2.05(s,3H);13C NMR(100MHz,CDCl3)(主要非对映异构体):δ166.6,147.1,144.8,142.6,140.4,139.9,137.3,135.6,133.8,133.3,130.9,129.0,128.6,128.3,128.0,127.5,126.3,125.9,125.8,125.3,124.9,123.3,123.0,51.6,21.3,21.0;HRMS(ESI-TOF):理论计算值:C26H21NNaO4 +[M+Na+]434.1363,实测值:434.1362;HPLC条件:Daicel ChiralpakAD色谱柱,1.流动相为异丙醇-正己烷混合液(v/v=5∶95),1mL/min,λ=220nm,主要非对映异构体tR(major)=10.127min,tR(minor)=9.632min,次要非对映异构体tR(maior)=8.326min。
实施例12:化合物I-12的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、4-氟-2-碘-1-甲基苯(23.6mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-12(白色固体,产率=40%,d.r.>20∶1,e.e.=99%)。1H NMR(400MHz,CDCl3):δ7.75(d,J=9.9Hz,1H),7.61(d,J=8.2Hz,1H),7.43-7.25(m,6H),7.21(d,J=8.7Hz,1H),7.18-7.13(m,1H),7.01(t,J=7.7Hz,1H),6.90(d,J=7.1Hz,1H),3.38(s,3H),2.25(s,3H),1.90(s,3H);13C NMR(100MHz,CDCl3):δ166.7,158.7(d,J=241.2Hz),139.3(d,J=3.2Hz),138.3,136.7(d,J=2.4Hz),136.2,133.3,133.2,133.1(d,J=3.3Hz),131.6,130.0,129.9,129.8,128.4(d,J=18.0Hz),128.3,127.9,127.6,127.2,126.6,125.6,125.5,124.9,114.0(d,J=22.4Hz),51.6,20.7,20.1;19F NMR(376MHz,CDCl3):δ-117.5;HRMS (ESI-TOF):理论计算值:C26H21FNaO2 +[M+Na+]407.1418,实测值:407.1413;HPLC条件:DaicelChiralpakAD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=220nm,tR(major)=5.216min,tR(minor)=4.732min。
实施例13:化合物I-13的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(46.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(7S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘芘(32.8mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-13(黄色固体,产率=57%,d.r.>20∶1,e.e.>99%)。1H NMR(400MHz,CDCl3):δ8.28(s,1H),8.23(dd,J=7.6,1.1Hz,1H),8.20-8.11(m,3H),8.01(t,J=7.6Hz,1H),7.84(dd,J=8.7,7.4Hz,2H),7.77-7.75(m,1H),7.44-7.35(m,4H),7.30-7.17(m,3H),7.16-7.08(m,2H),3.15(s,3H),2.19(s,3H);13C NMR(100MHz,CDCl3):δ167.1,142.5,138.7,138.1,136.6,133.5,133.35,133.33,133.0,131.6,130.9,130.6,130.6,129.9,128.2,127.9,127.81,127.76,127.7,127.4,126.91,126.86,126.6,126.1,125.5,125.3,125.2,125.0,124.9,124.0,51.4,21.6;HRMS(ESI-TOF):理论计算值:C35H24NaO2 +[M+Na+]499.1669,实测值:499.1661;HPLC条件:DaicelChiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=340nm,tR(major)=8.948min。
实施例14:化合物I-14的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、2-乙基苯基三氟硼酸钾(42.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-14(白色固体,产率=88%,d.r.>20∶1,e.e.=99%)。1H NMR(400MHz,CDCl3):δ7.94(d,J=8.3Hz,2H),7.59(dd,J=7.9,1.3Hz,1H),7.51-7.45(m,2H),7.37-7.31(m,2H),7.31-7.27(m,1H),7.22(dd,J=7.9,1.4Hz,1H),7.18-7.15(m,1H),7.15-7.10(m,1H),6.94(td,J=7.4,1.5Hz,1H),6.88(dd,J=7.7,1.5Hz,1H),3.56(s,3H),2.14(q,J=7.5Hz,2H),2.10(s,3H),1.01(t,J=7.6Hz,3H);13C NMR(100MHz,CDCl3):δ167.7,142.9,142.3,137.9,137.4,137.3,136.0,133.5,133.1,132.7,129.8,129.1,128.7,128.2,127.9,127.5,127.4,127.0,126.9,126.7,125.9,125.6,124.9,51.7,25.1,21.2,14.6;HRMS(ESI-TOF):理论计算值:C27H24NaO2 +[M+Na+]403.1669,实测值:403.1661;HPLC条件:Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=230nm,tR(major)=4.888min,tR(minor)=4.553min。
实施例15:化合物I-15的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、2-乙基苯基三氟硼酸钾(42.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-乙基苯甲酸甲酯(36.5mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-15(白色固体,产率=78%,d.r.>20∶1,e.e.=98%)。1H NMR(400MHz,CDCl3):δ7.96-7.92(m,2H),7.61(dd,J=7.8,1.4Hz,1H),7.53(d,J=8.5Hz,1H),7.50-7.46(m,1H),7.38-7.29(m,3H),7.23-7.12(m,3H),6.95-6.91(m,1H),6.86(dd,J=7.7,1.4Hz,1H),3.56(s,3H),2.47-2.35(m,2H),2.13(q,J=7.5Hz,2H),1.12(t,J=7.5Hz,3H),1.00(t,J=7.5Hz,3H);13C NMR(100MHz,CDCl3):δ167.8,144.0,142.9,141.5,137.4,137.0,136.0,133.0,132.7,131.8,129.6,129.3,129.0,128.2,127.8,127.5,127.4,127.2,127.0,126.2,125.9,125.6,124.8,51.7,26.8,25.0,15.6,14.6;HRMS(ESI-TOF):理论计算值:C28H26NaO2 +[M+Na+]417.1825,实测值:417.1828;HPLC条件:Daicel Chiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=1∶99),1mL/min,λ=230nm,tR(major)=8.605min,tR(minor)=9.656min。
实施例16:化合物I-16的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、2-乙基苯基三氟硼酸钾(42.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-((((叔丁基二甲基甲硅烷基)氧基)甲基)苯甲酸甲酯(53.9mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-16(黄色固体,产率=75%,d.r.>20∶1,e.e.>99%)。1H NMR(400MHz,CDCl3):δ7.96-7.92(m,2H),7.69-7.65(m,2H),7.51-7.47(m,2H),7.39-7.31(m,2H),7.29-7.12(m,3H),6.94-6.90(m,1H),6.86-6.83(m,1H),4.54-4.32(m,2H),3.55(s,3H),2.13(q,J=7.5Hz,2H),1.00(t,J=7.6Hz,3H),0.89(s,9H),-0.01(s,3H),-0.03(s,3H);13C NMR(100MHz,CDCl3):δ167.6,142.9,140.9,140.1,137.1,136.5,135.7,133.1,132.8,130.3,129.5,129.3,128.9,128.5,128.3,127.6,127.5,127.2,127.1,126.6,125.9,125.7,125.0,63.1,51.8,26.0,25.1,18.4,14.6,-5.18,-5.23;HRMS(ESI-TOF):理论计算值:C33H38SiNaO3 +[M+Na+]533.2482,实测值:533.2475;HPLC条件:Daicel ChiralpakIA色谱柱,流动相为异丙醇-正己烷混合液(v/v=1∶99),1mL/min,λ=230nm,tR(major)=7.128min。
实施例17:化合物I-17的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、2-乙基苯基三氟硼酸钾(42.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸叔丁酯(40.7mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-17(无色油状液体,产率=63%,d.r.>20∶1,e.e.>99%)。1H NMR(400MHz,CDCl3):δ7.94-7.90(m,2H),7.64-7.61(m,1H),7.50-7.45(m,2H),7.36-7.30(m,2H),7.21-7.14(m,3H),7.12-7.08(m,1H),7.00-6.95(m,2H),2.29(q,J=7.5Hz,2H),2.02(s,3H),1.31(s,9H),0.95(t,J=7.5Hz,3H);13C NMR(100MHz,CDCl3):δ166.9,143.3,141.5,137.7,137.6,137.3,136.5,133.4,132.9,132.8,132.0,129.7,129.4,128.12,128.05,127.6,127.5,127.0,126.8,126.5,125.8,125.5,124.6,81.2,28.2,25.7,21.2,14.9;HRMS(ESI-TOF):理论计算值:C30H30NaO2 +[M+Na+]445.2138,实测值:445.2128;Daicel Chiralpak IG色谱柱,流动相为异丙醇-正己烷混合液(v/v=1∶99),0.5mL/min,λ=254nm,tR(major)=8.130min。
实施例18:化合物I-18的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、2-乙基苯基三氟硼酸钾(42.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-1-甲基-3-硝基苯(32.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-18(黄色固体,产率=54%,d.r.>20∶1,e.e.=98%)。1H NMR(400MHz,CDCl3):δ7.97(dd,J=15.7,8.3Hz,2H),7.57-7.48(m,3H),7.43-7.34(m,3H),7.28(d,J=7.7Hz,1H),7.24-7.16(m,2H),6.90(td,J=7.5,1.4Hz,1H),6.73(dd,J=7.7,1.4Hz,1H),2.17(s,3H),2.17-2.11(m,1H),2.08-1.99(m,1H),1.05(t,J=7.5Hz,3H);13C NMR(100MHz,CDCl3):δ149.0,143.5,139.8,136.5,136.4,136.0,134.4,133.8,132.9,128.8,128.2,128.1,127.9,127.8,127.7,127.6,127.1,126.3,126.2,125.1,121.9,24.5,21.2,14.2;HRMS(ESI-TOF):理论计算值:C25H21NNaO2 +[M+Na+]390.1465,实测值:390.1465;Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=1∶99),1mL/min,λ=230nm,tR(maior)=9.080min,tR(minor)=7.817min。
实施例19:化合物I-19的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、2-乙基苯基三氟硼酸钾(42.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3,5-二甲基苯甲酸甲酯(36.5mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-19(白色固体,产率=86%,d.r.>20∶1,e.e.>99%)。1H NMR(400MHz,CDCl3):δ7.93(dd,J=8.4,2.4Hz,2H),7.49-7.45(m,2H),7.42(s,1H),7.37-7.30(m,2H),7.25-7.22(m,1H),7.20-7.16(m,1H),7.12(s,1H),6.98-6.94(m,1H),6.90(dd,J=7.7,1.6Hz,1H),3.55(s,3H),2.26(s,3H),2.15(q,J=7.5Hz,2H),2.07(s,3H),1.05-0.98(m,3H);13C NMR(100MHz,CDCl3):δ167.9,142.9,139.4,137.7,137.5,137.4,136.4,136.2,134.3,133.1,132.7,129.6,129.2,129.1,128.4,128.2,127.5,127.4,127.0,126.6,125.8,125.5,124.9,51.7,25.1,21.1,21.0,14.6;HRMS(ESI-TOF):理论计算值:C28H26NaO2 +[M+Na+]417.1825,实测值:417.1818;Daicel Chiralpak IG色谱柱,流动相为异丙醇-正己烷混合液(v/v=1∶99)(v/v),1mL/min,λ=230nm,tR(major)=8.735min。
实施例20:化合物I-20的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、2-乙基苯基三氟硼酸钾(42.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-5-氯-3-甲基苯甲酸甲酯(39.5mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-20(黄色固体,产率=61%,d.r.>20∶1,e.e.>99%)。1H NMR(400MHz,CDCl3):7.95-7.92(m,2H),7.58(dd,J=2.3,0.7Hz,1H),7.51-7.16(m,1H),7.42(d,J=8.5Hz,1H),7.37-7.27(m,3H),7.25-7.18(m,2H),7.00-6.95(m,1H),6.88-6.85(m,1H),3.57(s,3H),2.16-2.06(m,5H),1.00(t,J=7.6Hz,3H);13C NMR(100MHz,CDCl3):δ166.5,142.9,141.0,140.0,137.1,136.3,136.1,133.2,133.1,132.8,132.5,131.2,129.0,128.5,128.2,127.80,127.77,127.6,127.0,126.9,126.0,125.8,125.1,52.0,25.1,21.1,14.6;HRMS (ESI-TOF):理论计算值:C27H23ClNaO2 +[M+Na+]437.1279,实测值:437.1270;Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=1∶99),1mL/min,λ=230nm,tR(major)=8.767min。
实施例21:化合物I-21的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、2-乙基苯基三氟硼酸钾(42.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3,4-二甲基苯甲酸甲酯(36.5mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-21(黄色固体,产率=76%,d.r.>20∶1,e.e.=97%)。1H NMR(400MHz,CDCl3):δ7.96-7.90(m,2H),7.54(d,J=8.0Hz,1H),7.47(dd,J=8.3,6.1Hz,2H),7.38-7.28(m,2H),7.22-7.12(m,2H),7.02(d,J=8.0Hz,1H),6.96-6.92(m,1H),6.87(dd,J=7.7,1.4Hz,1H),3.55(s,3H),2.26(s,3H),2.19-2.10(m,2H),1.98(s,3H),1.00(t,J=7.6Hz,3H);13C NMR(100MHz,CDCl3):δ167.8,142.9,142.3,141.4,137.9,137.5,136.4,136.1,133.1,132.7,129.2,129.1,128.4,128.2,127.6,127.44,127.39,127.37,126.9,126.5,125.8,125.5,124.7,51.6,25.0,21.1,18.1,14.6;HRMS(ESI-TOF):理论计算值:C28H26NaO2 +[M+Na+]417.1825,实测值:417.1819;Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=1∶99),1mL/min,λ=230nm,rR(maior)=7.016min,rR(minor)=6.377min。
实施例22:化合物I-22的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、2-乙基苯基三氟硼酸钾(42.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯一2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、1-溴-2-萘甲酸甲酯(39.8mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-22(黄色固体,产率=50%,d.r.>20∶1,e.e.>99%)。1H NMR(400MHz,CDCl3):δ8.01(d,J=8.4Hz,2H),7.83(d,J=8.7Hz,1H),7.79(d,J=8.1Hz,1H),7.70(d,J=8.7Hz,1H),7.59(d,J=8.5Hz,1H),7.50(dd,J=12.6,7.9Hz,3H),7.43-7.30(m,3H),7.15(d,J=7.7Hz,1H),7.03-6.99(m,1H),6.62-6.60(m,1H),6.57-6.54(m,1H),3.64(s,3H),2.20(q,J=7.6Hz,2H),1.02(t,J=7.5Hz,3H);13C NMR(100MHz,CDCl3):δ167.7,142.7,142.4,137.3,137.0,136.0,134.7,133.8,133.1,132.9,129.6,129.3,128.7,128.3,127.8,127.6,127.4,127.1,127.0,126.44,126.43,126.3,126.1,125.8,124.4,51.9,25.1,14.6;HRMS(ESI-TOF):理论计算值:C30H24NaO2 +[M+Na+]439.1669,实测值:439.1661;Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=254nm,tR(major)=5.258min。
实施例23:化合物I-23的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(70.2mg,0.3mmol)、分子筛(40.0mg)和干燥的1,2-二氯乙烷(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-N,N,3-三甲基苯甲酰胺(36.3mg,0.15mmol)。所得混合物于130℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-23(无色油状液体,产率=80%,d.r.>20∶1,e.e.=98%)。1H NMR(400MHz,CDCl3):δ7.98(d,J=8.5Hz,1H),7.92(d,J=8.2Hz,1H),7.82(d,J=8.3Hz,1H),7.72(d,J=8.2Hz,1H),7.56(d,J=8.5Hz,1H),7.42(t,J=7.4Hz,2H),7.34-7.11(m,6H),7.05(t,J=7.6Hz,1H),6.99(d,J=8.5Hz,1H),6.74(d,J=7.6Hz,1H),2.39(s,3H),2.23(s,3H),1.16(s,3H);13C NMR(100MHz,CDCl3):δ170.0,140.9,138.3,137.6,136.6,134.8,134.2,133.7,133.4,133.1,132.9,130.81,130.2,128.3,128.1,127.9,127.60,127.55,127.3,127.2,126.1,125.9,125.6,125.5,125.0,37.8,34.5,21.4;HRMS(ESI-TOF):理论计算值:C30H26NO+[M+H+]416.2009,实测值:416.2002;HPLC条件:Daicel Chiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=15∶85)1mL/min,λ=220nm,tR(major)=11.733min,tR(minor)=14.632min。
实施例24:化合物I-24的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(70.2mg,0.3mmol)、分子筛(40.0mg)和干燥的1,2-二氯乙烷(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、(2-溴-3-甲基苯基)(吡咯烷-1-基)甲酮(40.2mg,0.15mmol)。所得混合物于130℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-24(无色油状液体,产率=63%,d.r.>20∶1,e.e.>99%)。1H NMR(400MHz,CDCl3):δ7.97(d,J=8.5Hz,1H),7.91(d,J=8.2Hz,1H),7.84(d,J=8.2Hz,1H),7.74(d,J=8.2Hz,1H),7.52(d,J=8.5Hz,1H),7.43-7.35(m,2H),7.33-7.23(m,3H),7.22-7.17(m,2H),7.15-7.06(m,2H),6.92(d,J=8.2Hz,1H),6.87(d,J=8.6Hz,1H),3.21-3.15(m,1H),2.81-2.73(m,2H),2.21(s,3H),1.43-1.23(m,2H),1.20-1.12(m,1H),0.98-0.92(m,1H),0.22-0.07(m,1H);13C NMR(100MHz,CDCl3):δ168.3,140.8,138.3,137.7,136.6,135.4,133.7,133.41,133.39,133.1,132.9,131.0,130.3,128.25,128.22,127.6,127.5,127.4,127.3,126.3,125.73,125.68,125.6,125.5,124.9,48.2,45.3,24.8,23.6,21.5;HRMS(ESI-TOF):理论计算值:C32H27NNaO+[M+Na+]464.1985,实测值:464.1975;HPLC条件:Daicel ChiralpakAD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=15∶85),1mL/min,λ=254nm,tR(major)=16.512min。
实施例25:化合物I-25的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(70.2mg,0.3mmol)、分子筛(40.0mg)和干燥的1,2-二氯乙烷(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、(2-溴-3-甲基苯基)二苯基氧化膦(55.7mg,0.15mmol)。所得混合物于130℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-25(黄色油状液体,产率=64%,d.r.>20∶1,e.e.>99%)。1H NMR(400MHz,CDCl3):δ8.04(d,J=8.5Hz,1H),7.91-7.85(m,2H),7.71-7.65(m,2H),7.45-7.37(m,6H),7.30-6.95(m,12H),6.81-6.72(m,3H),2.19(s,3H);13C NMR(100MHz,CDCl3):δ146.53,146.46,139.1,139.0,137.42,137.39,137.1,136.4,135.9,135.4,134.4,133.7,133.4,133.3,133.10,133.07,132.9,132.8,132.0,131.9,131.8,131.2,131.1,131.00,130.97,130.3,129.4,128.44,128.36,128.2,128.0,127.94,127.91,127.8,127.6,127.34,127.28,127.1,127.0,126.1,125.9,125.8,125.5,125.3,124.4,21.5(Due to C-P coupling and the complexitV ofthe spectrum,doublets in the aromatic region cannot be assigned and they arelisted as singlets);31P NMR(162MHz,CDCl3)δ:28.6;HRMS(ESI-TOF):理论计算值:C39H30OP+[M+H+]545.2029,实测值:545.2020;HPLC条件:Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=10∶90),1mL/min,λ=254nm,tR(major)=4.879min。
实施例26:化合物I-26的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、萘三氟硼酸钾(70.2mg,0.3mmol)、分子筛(40.0mg)和干燥的1,2-二氯乙烷(0.5mL),然后加入(7S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、(2-溴-3-甲基苯基)膦酸二乙酯(46.1mg,0.15mmol)。所得混合物于130℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-26(黄色油状液体,产率64%,d.r.>20∶1,e.e.>99%)。1H NMR(400MHz,CDCl3):δ7.98(d,J=8.4Hz,1H),7.94(d,J=8.1Hz,1H),7.75-7.69(m,3H),7.49-7.31(m,4H),7.30-7.10(m,7H),3.66-3.51(m,2H),3.49-3.39(m,1H),3.33-3.23(m,1H),2.14(s,3H),0.97(t,J=7.0Hz,3H),0.82(t,J=7.0Hz,3H);13C NMR(100MHz,CDCl3):δ144.7,144.6,138.2,138.1,137.84,137.80,136.4,135.5,133.5,133.41,133.40,133.2,133.0,130.7,130.6,129.5,128.4,128.14,128.09,128.0,127.7,127.6,127.5,127.4,127.0,126.9,126.2,125.9,125.6,125.5,125.0,124.7,61.4,61.3,61.22,61.16,21.7,21.6,16.24,16.18,16.1,16.0(Due to C-P coupling and the complexity of the spectrum,doublets in thearomatic region cannot be assigned and thev are listed as singlets);31P NMR(162MHz,CDCl3)δ:17.5;HRMS(ESI-TOF):理论计算值:C31H29NaO3P+[M+Na+]503,1747,实测值:503,1740;HPLC条件:Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=10∶90),1mL/min,λ=254nm,tR(major)=4.952min,tR(minor)=5.666min。
实施例27:化合物I-27的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、2-(苄氧基)苯基三氟硼酸钾(58mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-27(无色油状液体,产率=48%,d.r.>20∶1,e.e.=98%)。1H NMR(400MHz,CDCl3):δ7.94-7.90(m,2H),7.62(d,J=7.8Hz,1H),7.51-7.45(m,2H),7.38-7.34(m,2H),7.23-7.20(m,1H),7.17-7.13(m,5H),7.09(dd,J=7.5,1.8Hz,1H),6.91-6.88(m,2H),6.83-6.77(m,2H),4.88(q,J=12.9Hz,2H),3.60(s,3H),1.91(s,3H);13C NMR(100MHz,CDCl3):δ168.4,156.2,142.2,138.5,137.5,137.4,134.0,133.4,133.1,132.7,132.6,131.2,128.7,128.3,128.1,127.8,127.4,127.2,127.1,127.0,126.7,126.4,125.8,125.4,120.3,111.9,69.6,51.9,20.4;HRMS(ESI-TOF):理论计算值:C32H26NaO3 +[M+Na+]481.1774,实测值:481.1781;HPLC条件:Daicel Chiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=220nm,tR(major)=9.365min,tR(minor)=6.837min。
实施例28:化合物I-28的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、2-甲酰基三氟硼酸钾(42.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-28(无色油状液体,产率=47%,d.r.=2.7∶1,e.e.(主要非对映异构体)=98%,e.e.(次要非对映异构体)=98%)。1H NMR(400MHz,CDCl3)(主要非对映异构体):δ9.37(s,1H),8.03(d,J=8.4Hz,1H),7.98-7.95(m,2H),7.56-7.49(m,3H),7.40-7.28(m,5H),7.15(t,J=7.8Hz,1H),7.01-6.98(m,1H),3.52(s,3H),2.17(s,3H);13C NMR(100MHz,CDCl3)(主要非对映异构体):δ192.8,167.3,142.5,141.8,138.6,137.9,135.1,133.9,133.8,133.5,132.4,132.2,130.4,129.8,128.5,128.3,128.2,128.11,128.06,127.3,127.2,127.1,126.7,126.07,126.06,52.1,21.3;1H NMR(400MHz,CDCl3)(次要非对映异构体):δ9.60(s,1H),7.97(dd,J=13.0,8.3Hz,2H),7.90(d,J=7.7Hz,1H),7.63(d,J=7.6Hz,1H),7.51(t,J=7.5Hz,1H),7.46-7.32(m,5H),7.27(d,J=6.0Hz,1H),7.21(d,J=7.6Hz,1H),7.15(t,J=7.7Hz,1H),3.62(s,3H),1.95(s,3H).;13C NMR(100MHz,CDCl3)(次要非对映异构体):δ192.0,168.2,142.7,141.0,138.5,137.0,134.6,134.1,133.7,133.5,132.7,132.6,132.3,131.3,128.5,128.3,128.1,127.9,127.8,127.3,127.1,126.9,126.3,126.1,52.1,20.6;HRMS(ESI-TOF):理论计算值:C26H20NaO3 +[M+Na+]403.1305,实测值:403.1302;HPLC条件:DaicelChiralpakAD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=230nm,主要非对映异构体tR(major)=15.776min,tR(minor)=11.882min,次要非对映异构体tR(major)=9.834min,tR(minor)=10.999min。
实施例29:化合物I-29的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、3-氟-2-甲基苯基三氟硼酸钾(44mg,0.2mmOl)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-29(白色固体,产率=91%,d.r.=12∶1,e.e.(主要非对映异构体)=98%)。1H NMR(400MHz,CDCl3)(主要非对映异构体):δ7.98-7.94(m,2H),7.56(d,J=7.8Hz,1H),7.51-7.47(m,2H),7.40-7.36(m,1H),7.34-7.32(m,1H),7.30-7.28(m,1H),7.16(t,J=7.7Hz,1H),6.91-6.78(m,2H),6.65-6.59(m,1H),3.56(s,3H),2.14(s,3H),1.77(d,J=2.7Hz,3H);13C NMR(100MHz,CDCl3)(主要非对映异构体):δ167.5,161.5(d,J=244.1Hz),141.9,140.1(d,J=4.4Hz),137.9,137.5,134.5(d,J=2.5Hz),133.5,132.7,132.5,130.0,128.6,128.4,127.8,127.3,127.0,126.4,126.3,126.0(d,J=9.0Hz),125.7,125.0(d,J=17.0Hz),124.9(d,J=3.0Hz),113.7(d,J=22.6Hz),51.8,21.2,12.3(d,J=5.0Hz);19F NMR(376MHz,CDCl3):δ-116.2;HRMS(ESI-TOF):理论计算值:C26H21FNaO2 +[M+Na+]407.1418,实测值:407.1414;HPLC条件:Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=230nm,tR(major)=5.844min,tR(minor)=5.073min。
实施例30:化合物I-30的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、3-氯-2-甲基苯基三氟硼酸钾(46.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-30(白色固体,产率=83%,d.r.>20∶1,e.e.=98%)。1H NMR(400MHz,CDCl3):δ7.95(t,J=7.4Hz,2H),7.55(d,J=7.8Hz,1H),7.49(dd,J=8.2,5.6Hz,2H),7.37(q,J=6.2,4.5Hz,1H),7.32(d,J=7.6Hz,1H),7.29-7.22(m,1H),7.22-7.11(m,2H),6.84(t,J=7.8Hz,1H),6.73(d,J=7.6Hz,1H),3.57(s,3H),2.12(s,3H),1.87(s,3H);13C NMR(100MHz,CDCl3):δ167.4,141.8,139.8,137.8,137.4,135.7,135.2,135.0,133.5,132.7,132.5,130.1,128.6,128.4,128.2,127.95,127.89,127.3,127.0,126.5,126.3,126.0,125.7,51.8,21.2,18.1;HRMS(ESI-TOF):理论计算值:C26H21ClNaO2 +[M+Na+]423.1122,实测值:423.1115;HPLC条件:Daicel ChiralpakAD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=230nm,tR(major)=5.771min,tR(minor)=5.303min。
实施例31:化合物I-31的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、3-甲氧基-2-甲基苯基三氟硼酸钾(46mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-31(白色固体,产率=85%,d.r.=6.5∶1,e.e.(主要非对映异构体)=99%,e.e.(次要非对映异构体)=93%)。1H NMR(400MHz,CDCl3)(主要非对映异构体):δ7.93(d,J=8.5Hz,2H),7.55(d,J=7.8Hz,1H),7.47(t,J=7.4Hz,2H),7.34(dt,J=9.4,6.3Hz,3H),7.14(t,J=7.7Hz,1H),6.88(t,J=8.0Hz,1H),6.67(d,J=8.2Hz,1H),6.46(d,J=7.7Hz,1H),3.80(s,3H),3.54(s,3H),2.14(s,3H),1.71(s,3H);13C NMR(100MHz,CDCl3)(主要非对映异构体):δ167.6,157.6,142.2,138.9,137.9,137.2,135.9,133.4,132.8,132.6,130.2,128.7,128.3,127.7,126.82,126.80,126.75,126.4,126.1,125.53,125.47,121.6,108.7,55.4,51.8,21.2,13.7;HRMS(ESI-TOF):理论计算值:C27H24NaO3 +[M+Na+]419.1618,实测值:419.1609;HPLC条件:Daicel ChiralpakAD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=230nm,主要非对映异构体tR(major)=8.392min,tR(minor)=6.497min,次要非对映异构体tR(major)=6.972min,tR(minor)=6.146min。
实施例32:化合物I-32的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、4-甲氧基-1萘基三氟硼酸钾(52.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-32(黄色固体,产率=81%,>d.r.=20∶1,e.e.=99%)。1H NMR(400MHz,CDCl3):δ8.23(d,J=8.4Hz,1H),8.00(dd,J=23.2,8.4Hz,2H),7.55(d,J=8.4Hz,1H),7.45(t,J=7.4Hz,1H),7.35(dt,J=14.2,6.9Hz,3H),7.27-7.14(m,4H),7.06(t,J=7.7Hz,1H),6.96(d,J=7.9Hz,1H),6.58(d,J=7.9Hz,1H),3.93(s,3H),3.27(s,3H),2.21(s,3H);13C NMR(100MHz,CDCl3):δ167.2,154.8,142.6,138.7,137.6,134.8,133.9,133.8,133.3,132.8,129.8,128.7,128.5,128.2,127.7,127.5,127.3,127.2,126.8,126.7,126.0,125.8,125.5,125.3,124.7,121.9,103.1,55.4,51.4,21.3;HRMS(ESI-TOF):理论计算值:C30H24NaO3 +[M+Na+]455.1618,实测值:455.1611;HPLC条件:Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=230nm,tR(major)=15.718min,tR(minor)=10.031min。
实施例33:化合物I-33的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、4-溴-1萘基三氟硼酸钾(62.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-33(黄色固体,产率=76%,d.r.>20∶1,e.e.=99%)。1H NMR(400MHz,CDCl3):δ8.21(d,J=8.5Hz,1H),8.05(d,J=8.5Hz,1H),8.01-7.95(m,1H),7.55(dd,J=8.1,6.4Hz,2H),7.51-7.44(m,2H),7.36-7.30(m,2H),7.26-7.24(m,2H),7.23-7.19(m,1H),7.11-7.04(m,2H),6.93(d,J=7.7Hz,1H),3.29(s,3H),2.19(s,3H);13C NMR(100MHz,CDCl3):δ167.1,142.0,138.5,137.5,136.8,134.1,133.7,133.6,133.3,132.7,131.7,129.6,129.2,128.7,128.32,128.27,127.9,127.7,127.3,127.1,127.0,126.9,126.3,126.1,125.7,122.5,51.5,21.2;HRMS(ESI-TOF):理论计算值:C29H21BrNaO2 +[M+Na+]503.0617,实测值:503.0612;HPLC条件:Daicel ChiralpakAD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=230nm,tR(major)=8.291min,tR(minor)=7.315min。
实施例34:化合物I-34的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、9-菲基三氟硼酸钾(56.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-34(黄色固体,产率=80%,d.r.=10∶1,主要非对映异构体e.e.>99%,次要非对映异构体e.e.>99%)。
1H NMR(400MHz,CDCl3)(主要非对映异构体):δ8.64(dd,J=12.6,8.3Hz,2H),8.06(d,J=8.5Hz,1H),7.98(d,J=8.2Hz,1H),7.63-7.43(m,6H),7.39(s,1H),7.33-7.27(m,2H),7.27-7.23(m,2H),7.20(d,J=4.1Hz,2H),6.94(t,J=7.7Hz,1H),3.33(s,3H),2.27(s,3H);13C NMR(100MHz,CDCl3)(主要非对映异构体):δ167.3,142.2,138.5,137.5,135.3,134.6,133.6,133.4,132.8,132.0,131.4,130.1,129.6,128.8,128.54,128.47,128.3,127.7,127.6,127.5,127.2,126.9,126.6,126.5,126.2,126.1,126.0,125.7,122.7,122.6,51.6,21.3;HRMS(ESI-TOF):理论计算值:C33H24NaO2 +[M+Na+]475.1669,实测值:475.1661;HPLC条件:Daicel Chiralpak IG色谱柱,流动相为异丙醇-正己烷混合液(v/v=5∶95),1mL/min,λ=230nm,主要非对映异构体tR(major)=10.045min,次要非对映异构体tR(major)=8.072min。
实施例35:化合物I-35的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、1-芘基三氟硼酸钾(62mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-35(黄色固体,产率=86%,d.r.=8.3∶1,e.e.(主要非对映异构体)=98%,e.e.(次要非对映异构体)=97%)。1H NMR(400MHz,CDCl3)(主要非对映异构体):δ8.17(dd,J=7.8,1.1Hz,1H),8.12(d,J=8.5Hz,1H),8.11-8.09(m,1H),8.05-8.02(m,2H),8.00-7.92(m,3H),7.82(d,J=9.2Hz,1H),7.64(d,J=8.5Hz,1H),7.60(d,J=7.9Hz,1H),7.51(d,J=9.2Hz,1H),7.49-7.45(m,1H),7.35-7.29(m,1H),7.18(td,J=7.7,7.0,1.3Hz,2H),7.09-7.05(m,1H),6.98(t,J=7.7Hz,1H),3.30(s,3H),2.33(s,3H);13C NMR(100MHz,CDCl3)(主要非对映异构体):δ167.1,142.4,138.7,137.7,135.1,134.1,133.7,133.5,132.8,131.4,130.9,130.6,130.2,129.9,128.7,128.3,127.7,127.6,127.5,127.4,127.3,127.2,127.0,126.8,126.6,126.2,126.0,125.7,125.1,125.0,124.8,124.6,124.4,51.4,21.4;HRMS(ESI-TOF):理论计算值:C35H24NaO2 +[M+Na+]499.1669,实测值:499.1660;HPLC条件:DaicelChiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=230nm,主要非对映异构体rR(major)=15.122min,tR(minor)=11.085min,次要非对映异构体tR(major)=8.477min,tR(minor)=7.195min。
实施例36:化合物I-36的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、1H-吲哚-1-甲酸叔丁酯-4-三氟硼酸钾(64.6mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-36(无色液体,产率=41%,d.r.>20∶1,e.e.=98%)。1H NMR(400MHz,CDCl3):δ7.98(dd,J=18.5,8.3Hz,3H),7.52-7.39(m,4H),7.34(d,J=7.6Hz,1H),7.27(d,J=4.3Hz,2H),7.08(dt,J=22.2,7.8Hz,2H),6.76(d,J=7.3Hz,1H),5.94(d,J=3.8Hz,1H),3.39(s,3H),2.23(s,3H),1.66(s,9H);13C NMR(100MHz,CDCl3):δ167.2,150.0,142.6,137.92,137.85,134.5,133.6,132.93,132.90,131.6,131.1,130.0,128.3,127.8,127.5,127.0,126.9,126.0,125.6,125.2,123.9,123.5,114.2,108.1,83.8,51.6,28.4,21.4;HRMS(ESI-TOF):理论计算值:C32H29NNaO4 +[M+Na+]514.1989,实测值:514.1988;HPLC条件:DaicelChiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=220nm,tR(major)=6.515min,tR(minor)=8.246min。
实施例37:化合物I-37的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、5-喹啉三氟硼酸钾(47mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-37(无色液体,产率=48%,d.r.>20∶1,e.e.=97%)。1H NMR(400MHz,CDCl3):δ8.83(dd,J=4.2,1.8Hz,1H),8.07(d,J=8.4Hz,1H),7.98(t,J=8.7Hz,2H),7.61(dd,J=8.6,1.7Hz,1H),7.56(d,J=8.5Hz,1H),7.48(t,J=7.1Hz,2H),7.34(t,J=8.3Hz,2H),7.26-7.21(m,1H),7.18-7.11(m,2H),7.09-7.02(m,2H),3.29(s,3H),2.21(s,3H);13C NMR(100MHz,CDCl3):δ167.0,150.1,148.2,142.2,138.9,137.7,137.0,136.1,133.8,133.4,133.3,132.8,129.3,129.1,128.8,128.5,128.4,128.1,128.0,127.4,127.1,126.8,126.4,125.8,120.4,51.5,21.3;HRMS(ESI-TOF):理论计算值:C28H22NO2 +[M+H+]404.1645,实测值:404.1646;HPLC条件:Daicel Chiralpak IA色谱柱,流动相为异丙醇-正己烷混合液(v/v=5∶95),1mL/min,λ=220nm,tR(major)=15.456min,tR(minor)=17.875min。
实施例38:化合物I-38的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、6-甲氧基-2-甲基吡啶-3-三氟硼酸钾(40.4mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-38(无色液体,产率=53%,d.r.>20∶1,e.e.=98%)。1H NMR(400MHz,CDCl3):δ7.95(dd,J=8.4,4.0Hz,2H),7.61(d,J=7.7Hz,1H),7.52-7.44(m,2H),7.40(t,J=8.2Hz,1H),7.36-7.31(m,2H),7.18(t,J=7.7Hz,1H),7.00(d,J=8.4Hz,1H),6.32(d,J=8.4Hz,1H),3.90(s,3H),3.57(s,3H),2.11(s,3H),1.99(s,3H);13C NMR(100MHz,CDCl3):δ167.5,162.7,155.1,142.0,140.1,138.0,137.6,133.8,133.7,132.9,132.8,130.1,128.6,128.1,127.4,127.2,126.4,126.3,125.7,125.4,106.8,53.4,51.8,23.0,21.2;HRMS(ESI-TOF):理论计算值:C26H24NO3 +[M+H+]398.1751,实测值:398.1755;HPLC条件:DaicelChiralpak IG色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=254nm,tR(major)=7.127min,tR(minor)=7.610min。
实施例39:化合物I-39的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、二苯并[b,d]呋喃-4-三氟硼酸钾(54.8mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯-2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-39(无色液体,产率=86%,d.r.>20∶1,e.e.=98%)。1H NMR(400MHz,CDCl3):δ8.05(d,J=8.4Hz,1H),8.00(d,J=8.2Hz,1H),7.92(d,J=7.6Hz,1H),7.84(dd,J=7.5,1.4Hz,1H),7.56(d,J=9.2Hz,1H),7.53-7.49(m,1H),7.47(d,J=8.5Hz,1H),7.41-7.27(m,5H),7.23(t,J=7.5Hz,1H),7.08(d,J=7.7Hz,1H),7.01(t,J=7.6Hz,1H),3.64(s,3H),2.07(s,3H);13C NMR(100MHz,CDCl3):δ168.3,155.9,154.3,141.7,138.4,138.2,133.5,132.9,132.8,131.8,131.0,130.1,128.4,128.1,127.8,127.1,126.9,126.7,126.4,125.8,124.4,123.9,123.1,122.7,122.4,120.8,120.0,111.7,52.0,20.5;HRMS(ESI-TOF):理论计算值:C31H23O3 +[M+H+]443.1642,实测值:443.1641;HPLC条件:Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=220nm,tR(major)=8.187min,tR(minor)=9.478min。
实施例40:化合物I-40的制备
在氩气保护下,向干燥并装有磁力搅拌子的反应管中加入醋酸钯(2.3mg,0.01mmol)、碳酸钾(34.6mg,0.25mmol)、苯并[b]噻吩-3-三氟硼酸钾(48mg,0.2mmol)、分子筛(40.0mg)和干燥的四氢呋喃(0.5mL),然后加入(1S,4R)-2-降冰片烯一2-甲酸甲酯(7.6mg,0.05mmol)、1-碘萘(25.4mg,0.1mmol)、2-溴-3-甲基苯甲酸甲酯(34.4mg,0.15mmol)。所得混合物于110℃、氩气保护氛围下反应24小时。反应结束后冷却至室温,混合物用硅藻土过滤,乙酸乙酯洗涤,减压蒸馏除去溶剂,柱层析分离纯化得化合物I-40(无色液体,产率=44%,d.r.>20∶1,e.e.=97%)。1H NMR(400MHz,CDCl3):δ8.04(d,J=8.4Hz,1H),7.98(d,J=8.2Hz,1H),7.81(d,J=8.0Hz,1H),7.55-7.46(m,2H),7.44(d,J=9.1Hz,1H),7.40-7.36(m,2H),7.34-7.27(m,2H),7.20-7.13(m,3H),6.87(s,1H),3.22(s,3H),2.21(s,3H);13C NMR(100MHz,CDCl3):δ167.0,142.5,139.8,139.4,139.2,137.6,134.3,133.5,133.1,133.0,130.4,129.7,128.4,128.3,128.0,127.9,127.0,126.9,126.2,125.8,124.53,124.46,124.1,123.7,122.6,51.4,21.3;HRMS(ESI-TOF):理论计算值:C27H21O2S+[M+H+]409.1257,实测值:409.1249;HPLC条件:Daicel Chiralpak AD-H色谱柱,流动相为异丙醇-正己烷混合液(v/v=2∶98),1mL/min,λ=220nm,tR(maior)=11.513min,tR(minor)=8.184min。
表6实施例1~40制备的1,2-双轴手性联芳基化合物
以上所述,仅为本发明较佳的具体实施方式,但本发明保护的范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内所做的任何修改,等同替换和改进等,均应包含在发明的保护范围之内。
Claims (10)
1.一种1,2-双轴手性联芳基化合物,其特征在于,具有通式(I)所示的结构:
其中:
R1~R7分别独立地选自芳基、杂芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、膦基、苄氧基、烯基、炔基、Cl、F中的一种,且R2、R3不相同;或
R4、R7独立地为Br;或
(i)R1与1~3个R4之间、(ii)R3与2~3个R5之间、(iii)R6与1~3个R7之间可互相连接形成环状结构Ar1,Ar1为取代或未取代的苯环、杂环芳环、萘环、菲环、芘环、吡啶环、吲哚环、二苯并呋喃环、苯并噻吩环、喹啉环中的一种,Ar1上的取代基为芳基、杂芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、膦基、苄氧基、烯基、炔基、Cl、F中的一种或多种;
L代表O、S、N、C=C、C=O、C=S、C=N中的一种;
m表示R4的个数,0≤m≤3;当m≥2时,多个R4基团相同或不同;
n表示R5的个数,0≤n≤3;当n≥2时,多个R5基团相同或不同;
p表示R7的个数,0≤p≤3;当p≥2时,多个R7基团相同或不同。
3.根据权利要求2所述的1,2-双轴手性联芳基化合物的制备方法,其特征在于:当R1与1~3个R4之间互相连接形成环状结构Ar1时,所述不对称芳基碘化物A的结构式为
R4、R4b、R4c、R4d分别独立地选自芳基、杂芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、膦基、苄氧基、烯基、炔基、Cl、F中的一种;
m1代表R4的个数,0≤m1≤2;当m1≥2时,多个R4基团相同或不同;
m2表示R4a的个数,0≤m2≤3;当m2≥2时,多个R4a基团相同或不同;
m3表示R4b的个数,0≤m3≤3;当m3≥2时,多个R4b基团相同或不同;
m4表示R4c的个数,0≤m4≤3;当m4≥2时,多个R4c基团相同或不同。
4.根据权利要求2所述的1,2-双轴手性联芳基化合物的制备方法,其特征在于:R2为吸电子基,选自酯基、醛基、羧基、氰基、硝基、磺酰基、膦基中的一种,R3为给电子基。
6.根据权利要求2所述的1,2-双轴手性联芳基化合物的制备方法,其特征在于:当R6与1~3个R7之间互相连接形成环状结构Ar1时,所述不对称三氟硼酸有机盐C的结构式为
其中,R7、R7a、R7b、R7c分别独立地选自芳基、杂芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、膦基、苄氧基、烯基、炔基、Cl、F、Br中的一种;
p1代表R7的个数,0≤p1≤3;当p1≥2时,多个R7基团相同或不同;
p2代表R7a的个数,0≤p2≤4;当p2≥2时,多个R7a基团相同或不同;
p3代表R7b的个数,0≤p3≤4;当p3≥2时,多个R7b基团相同或不同;
p4代表R7c的个数,0≤p4≤4;当p4≥2时,多个R7c基团相同或不同。
8.根据权利要求2所述的1,2-双轴手性联芳基化合物的制备方法,其特征在于:所述钯催化剂选自Pd(PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、PdI2、[Pd(allyl)Cl]2中的任意一种或几种;反应温度为105~120℃;所述碱选自碳酸钠、碳酸钾、碳酸铯、醋酸钠、醋酸钾、醋酸铯、磷酸三钾、甲酸钾、氢氧化钠、叔丁醇钠中的任意一种或几种;所述有机溶剂选自甲醇、乙醇、异丙醇、叔丁醇、四氢呋喃、2-甲基四氢呋喃、乙醚、二甲基乙二醚、甲基叔丁基醚、1,4-二氧六烷、1,3-二氧六烷、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、C4-12的饱和烷烃、C3-12的氟代或者氯代烷烃、苯、甲苯、二甲苯、三甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、N-甲基吡咯烷酮、乙腈、C3-12的饱和烷基腈中的任意一种或几种。
9.根据权利要求8所述的1,2-双轴手性联芳基化合物的制备方法,其特征在于:所述钯催化剂为醋酸钯,反应温度为105~110℃,所述碱为碳酸钾。
10.权利要求1所述的1,2-双轴手性联芳基化合物的应用。
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CN114149396A (zh) * | 2021-12-23 | 2022-03-08 | 山东第一医科大学(山东省医学科学院) | 一种手性双环γ-丁内酯类化合物及其应用 |
CN116621802A (zh) * | 2023-05-17 | 2023-08-22 | 湖南师范大学 | 一种钯催化级联环化反应合成3,4-二苯并异香豆素及其衍生物的方法 |
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CN114085201A (zh) * | 2021-12-23 | 2022-02-25 | 山东第一医科大学(山东省医学科学院) | 一种手性双环γ-丁内酯类化合物的制备方法 |
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CN117623839A (zh) * | 2023-11-28 | 2024-03-01 | 华中师范大学 | 一种联芳基轴手性吡咯化合物及其合成方法和应用 |
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