CN110117237A - A kind of preparation method of aromatic nitriles or alkenyl nitrile compounds - Google Patents
A kind of preparation method of aromatic nitriles or alkenyl nitrile compounds Download PDFInfo
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- CN110117237A CN110117237A CN201810113897.7A CN201810113897A CN110117237A CN 110117237 A CN110117237 A CN 110117237A CN 201810113897 A CN201810113897 A CN 201810113897A CN 110117237 A CN110117237 A CN 110117237A
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- Prior art keywords
- linear
- branched alkyl
- ring
- alkyl group
- formula
- Prior art date
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- -1 aromatic nitriles Chemical class 0.000 title claims abstract description 192
- 238000002360 preparation method Methods 0.000 title claims abstract description 68
- 239000002904 solvent Substances 0.000 claims abstract description 90
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 83
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 48
- 125000003118 aryl group Chemical group 0.000 claims abstract description 45
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 39
- 238000006880 cross-coupling reaction Methods 0.000 claims abstract description 37
- 239000000654 additive Substances 0.000 claims abstract description 24
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 24
- 239000011701 zinc Substances 0.000 claims abstract description 24
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 23
- 230000000996 additive effect Effects 0.000 claims abstract description 16
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 13
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical group [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000011261 inert gas Substances 0.000 claims abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 144
- 125000000217 alkyl group Chemical group 0.000 claims description 86
- 238000006243 chemical reaction Methods 0.000 claims description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 64
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 150000002367 halogens Chemical class 0.000 claims description 37
- 239000003446 ligand Substances 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 26
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 21
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 claims description 21
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 21
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical group [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 229910052740 iodine Inorganic materials 0.000 claims description 17
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 17
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 15
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 239000011630 iodine Substances 0.000 claims description 14
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 13
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 13
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 13
- 229940113088 dimethylacetamide Drugs 0.000 claims description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 12
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 12
- 239000007789 gas Substances 0.000 claims description 12
- UJNZOIKQAUQOCN-UHFFFAOYSA-N methyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C)C1=CC=CC=C1 UJNZOIKQAUQOCN-UHFFFAOYSA-N 0.000 claims description 12
- 125000003367 polycyclic group Chemical group 0.000 claims description 12
- 125000005418 aryl aryl group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 10
- 229910021588 Nickel(II) iodide Inorganic materials 0.000 claims description 9
- 150000008282 halocarbons Chemical class 0.000 claims description 9
- 150000002825 nitriles Chemical class 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 8
- XINWHKIKKFDJLM-UHFFFAOYSA-N butane;diphenylphosphane Chemical compound CCCC.C=1C=CC=CC=1PC1=CC=CC=C1.C=1C=CC=CC=1PC1=CC=CC=C1 XINWHKIKKFDJLM-UHFFFAOYSA-N 0.000 claims description 8
- 125000002837 carbocyclic group Chemical group 0.000 claims description 8
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 8
- TWWJJVNUZQLCPD-UHFFFAOYSA-N diphenylphosphane;methane Chemical compound C.C=1C=CC=CC=1PC1=CC=CC=C1 TWWJJVNUZQLCPD-UHFFFAOYSA-N 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 8
- 150000003462 sulfoxides Chemical class 0.000 claims description 8
- HASCQPSFPAKVEK-UHFFFAOYSA-N dimethyl(phenyl)phosphine Chemical compound CP(C)C1=CC=CC=C1 HASCQPSFPAKVEK-UHFFFAOYSA-N 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 229910052786 argon Inorganic materials 0.000 claims description 6
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 5
- BFSQJYRFLQUZKX-UHFFFAOYSA-L nickel(ii) iodide Chemical compound I[Ni]I BFSQJYRFLQUZKX-UHFFFAOYSA-L 0.000 claims description 5
- 229910052701 rubidium Inorganic materials 0.000 claims description 5
- 235000009518 sodium iodide Nutrition 0.000 claims description 5
- 229910021587 Nickel(II) fluoride Inorganic materials 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 4
- STCDDNDGEFVYKE-UHFFFAOYSA-N diphenylphosphane;propane Chemical compound CCC.C=1C=CC=CC=1PC1=CC=CC=C1.C=1C=CC=CC=1PC1=CC=CC=C1 STCDDNDGEFVYKE-UHFFFAOYSA-N 0.000 claims description 4
- CRHWEIDCXNDTMO-UHFFFAOYSA-N ditert-butylphosphane Chemical compound CC(C)(C)PC(C)(C)C CRHWEIDCXNDTMO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052734 helium Inorganic materials 0.000 claims description 4
- 239000001307 helium Substances 0.000 claims description 4
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 4
- 238000011065 in-situ storage Methods 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 229910052754 neon Inorganic materials 0.000 claims description 4
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 3
- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical compound [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 230000006641 stabilisation Effects 0.000 claims description 2
- 238000011105 stabilization Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims 2
- DLIJPAHLBJIQHE-UHFFFAOYSA-N butylphosphane Chemical compound CCCCP DLIJPAHLBJIQHE-UHFFFAOYSA-N 0.000 claims 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims 2
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 claims 1
- ZOAMZFNAPHWBEN-UHFFFAOYSA-N 2-$l^{1}-oxidanylpropane Chemical compound CC(C)[O] ZOAMZFNAPHWBEN-UHFFFAOYSA-N 0.000 claims 1
- 125000005605 benzo group Chemical group 0.000 claims 1
- 150000004950 naphthalene Chemical class 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 125000004434 sulfur atom Chemical group 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 14
- 239000003054 catalyst Substances 0.000 abstract description 10
- 125000000524 functional group Chemical group 0.000 abstract description 7
- 238000010959 commercial synthesis reaction Methods 0.000 abstract description 3
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 176
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 148
- 238000005160 1H NMR spectroscopy Methods 0.000 description 88
- 239000000047 product Substances 0.000 description 59
- 239000003480 eluent Substances 0.000 description 54
- 239000007787 solid Substances 0.000 description 51
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 39
- 238000010898 silica gel chromatography Methods 0.000 description 31
- 238000004587 chromatography analysis Methods 0.000 description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 229960001866 silicon dioxide Drugs 0.000 description 23
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 13
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 150000002989 phenols Chemical class 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XGCDBGRZEKYHNV-UHFFFAOYSA-N 1,1-bis(diphenylphosphino)methane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CP(C=1C=CC=CC=1)C1=CC=CC=C1 XGCDBGRZEKYHNV-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- 238000012805 post-processing Methods 0.000 description 4
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 4
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 4
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- FRUBCADIVWBPBB-UHFFFAOYSA-N (4-acetylphenyl) methanesulfonate Chemical class CC(=O)C1=CC=C(OS(C)(=O)=O)C=C1 FRUBCADIVWBPBB-UHFFFAOYSA-N 0.000 description 2
- BZKNVCHUULQHAT-UHFFFAOYSA-N (4-methoxyphenyl) methanesulfonate Chemical class COC1=CC=C(OS(C)(=O)=O)C=C1 BZKNVCHUULQHAT-UHFFFAOYSA-N 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
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- 125000003342 alkenyl group Chemical group 0.000 description 2
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- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
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- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
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- 238000000926 separation method Methods 0.000 description 2
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- 230000001988 toxicity Effects 0.000 description 2
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- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 2
- VXQHRUVOGJPQRG-UHFFFAOYSA-N (2,4,6-trimethylphenyl) trifluoromethanesulfonate Chemical group CC1=CC(C)=C(OS(=O)(=O)C(F)(F)F)C(C)=C1 VXQHRUVOGJPQRG-UHFFFAOYSA-N 0.000 description 1
- SRXCBGBYJGNHOS-UHFFFAOYSA-N (4-acetylphenyl) 4-methylbenzenesulfonate Chemical compound C1=CC(C(=O)C)=CC=C1OS(=O)(=O)C1=CC=C(C)C=C1 SRXCBGBYJGNHOS-UHFFFAOYSA-N 0.000 description 1
- FSVKGZPZEVFTQE-UHFFFAOYSA-N (4-acetylphenyl) N,N-dimethylsulfamate Chemical compound CN(C)S(=O)(=O)OC1=CC=C(C(C)=O)C=C1 FSVKGZPZEVFTQE-UHFFFAOYSA-N 0.000 description 1
- RUMMIUOXQGFCEP-UHFFFAOYSA-N (4-acetylphenyl) trifluoromethanesulfonate Chemical compound CC(=O)C1=CC=C(OS(=O)(=O)C(F)(F)F)C=C1 RUMMIUOXQGFCEP-UHFFFAOYSA-N 0.000 description 1
- UCYKCEOQFYKRAG-UHFFFAOYSA-N (4-benzoylphenyl) methanesulfonate Chemical class C1=CC(OS(=O)(=O)C)=CC=C1C(=O)C1=CC=CC=C1 UCYKCEOQFYKRAG-UHFFFAOYSA-N 0.000 description 1
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 1
- HFIIWQPDFQIATN-UHFFFAOYSA-N 1-chloro-4-fluorosulfonyloxybenzene Chemical compound FS(=O)(=O)Oc1ccc(Cl)cc1 HFIIWQPDFQIATN-UHFFFAOYSA-N 0.000 description 1
- KRFXUAVCNYFMJE-UHFFFAOYSA-N 1-fluorosulfonyloxy-4-methoxybenzene Chemical compound COC1=CC=C(OS(F)(=O)=O)C=C1 KRFXUAVCNYFMJE-UHFFFAOYSA-N 0.000 description 1
- QQLIGMASAVJVON-UHFFFAOYSA-N 1-naphthalen-1-ylethanone Chemical compound C1=CC=C2C(C(=O)C)=CC=CC2=C1 QQLIGMASAVJVON-UHFFFAOYSA-N 0.000 description 1
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 description 1
- FBMYKMYQHCBIGU-UHFFFAOYSA-N 2-[2-hydroxy-3-[[1-(1h-indol-3-yl)-2-methylpropan-2-yl]amino]propoxy]benzonitrile Chemical compound C=1NC2=CC=CC=C2C=1CC(C)(C)NCC(O)COC1=CC=CC=C1C#N FBMYKMYQHCBIGU-UHFFFAOYSA-N 0.000 description 1
- RIYSFSQPHCAGLS-UHFFFAOYSA-N 2-amino-3,5-dinitrobenzonitrile Chemical compound NC1=C(C#N)C=C([N+]([O-])=O)C=C1[N+]([O-])=O RIYSFSQPHCAGLS-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical class [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
- KQDJTBPASNJQFQ-UHFFFAOYSA-N 2-iodophenol Chemical compound OC1=CC=CC=C1I KQDJTBPASNJQFQ-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- IORVOBJVFPHSKR-UHFFFAOYSA-N 3-bromo-2,6-difluorobenzonitrile Chemical compound FC1=CC=C(Br)C(F)=C1C#N IORVOBJVFPHSKR-UHFFFAOYSA-N 0.000 description 1
- YKAYMASDSHFOGI-UHFFFAOYSA-N 4-phenylcyclohexan-1-one Chemical compound C1CC(=O)CCC1C1=CC=CC=C1 YKAYMASDSHFOGI-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 125000006414 CCl Chemical group ClC* 0.000 description 1
- TVZCRIROJQEVOT-CABCVRRESA-N Cromakalim Chemical compound N1([C@@H]2C3=CC(=CC=C3OC([C@H]2O)(C)C)C#N)CCCC1=O TVZCRIROJQEVOT-CABCVRRESA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 238000005609 Rosenmund-von Braun cyanation reaction Methods 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 description 1
- CUBJNKUIUXLFOT-UHFFFAOYSA-N [NH4+].[I-].C(C)[PH3+].[I-] Chemical compound [NH4+].[I-].C(C)[PH3+].[I-] CUBJNKUIUXLFOT-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 1
- 229960001667 alogliptin Drugs 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000008361 aminoacetonitriles Chemical class 0.000 description 1
- 229940107816 ammonium iodide Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 229940124411 anti-hiv antiviral agent Drugs 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 150000001500 aryl chlorides Chemical class 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229950005341 bucindolol Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 229950004210 cromakalim Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- BOUYBUIVMHNXQB-UHFFFAOYSA-N dicyclohexyl(2-dicyclohexylphosphanylethyl)phosphane Chemical compound C1CCCCC1P(C1CCCCC1)CCP(C1CCCCC1)C1CCCCC1 BOUYBUIVMHNXQB-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 1
- 229960002049 etravirine Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 1
- 229960005101 febuxostat Drugs 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 1
- 229950008835 neratinib Drugs 0.000 description 1
- 150000002815 nickel Chemical class 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000002896 organic halogen compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229910001753 sapphirine Inorganic materials 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000033772 system development Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- BYGOPQKDHGXNCD-UHFFFAOYSA-N tripotassium;iron(3+);hexacyanide Chemical compound [K+].[K+].[K+].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] BYGOPQKDHGXNCD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/16—Preparation of carboxylic acid nitriles by reaction of cyanides with lactones or compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/31—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/34—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring with cyano groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by unsaturated carbon chains
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
Abstract
The invention discloses the preparation methods of a kind of aromatic nitriles or alkenyl nitrile compounds.Preparation method of the invention is the following steps are included: under inert gas protection; in a solvent; under the conditions of existing for nickel complex, metallic zinc and the additive; the aryl as shown in Formula II or heteroaryl sulfonates compounds and cyanylation agent are subjected to cross-coupling reaction as follows; or the olefin sulfonic acid ester type compound as shown in IV and cyanylation agent are subjected to cross-coupling reaction as follows；Wherein, the additive is 4-dimethylaminopyridine (DMAP), and the cyanylation agent is zinc cyanide.Preparation method of the invention can be with cheap catalyst system, it is simple and direct efficiently to realize the cyanalation of aromatic yl sulphonate, heteroaryl sulfonates or olefin sulfonic acid ester, but also there is good functional group compatibility and substrate universality, to realize that the commercial synthesis of aromatic nitriles or alkenyl nitrile compounds provides better application prospect and use value.
Description
Technical field
The present invention relates to organic chemistry fileds, and in particular to the preparation method of a kind of aromatic nitriles or alkenyl nitrile compounds.
Background technique
As reaction intermediate excellent in organic chemistry, aromatic nitrile compounds be widely used in biology,
In the fields such as medicine, pesticide, functional material.If 2,4- dinitro -6- cyano-aniline is for manufacturing excellent sapphirine diazonium
The important intermediate of dyestuff；The bromo- 2,6- difluorobenzonitrile of 4- is to synthesize a kind of excellent liquid crystal with moderate dielectric anisotropy
The important synthetic intermediate of material；Many natural products and clinical medicine all contain cyano group, such as antineoplastic simultaneously
Letrozole, beta inhibitor Bucindolol, kinase inhibitor Neratinib, cardiovascular drug cromakalim, Anti-HIV agents
Etravirine, gout suppressant Febuxostat, antidepressants Citalopram, diabetes medicament alogliptin etc..Cyano
Why it is widely used in pharmaceutical chemistry research, what this was mainly determined by the special nature of cyano.Cyano has opposite
Lesser volume (about the 1/8 of methyl), furthermore cyano has strong electron-withdrawing feature, so that cyano becomes a kind of good
Hydrogen bond receptor, the critical amino acid residues that can be deep into target proteins depths and active site form strong hydrogen bond phase interaction
With；Meanwhile cyano polarizability is high, promotes to generate polar interaction, therefore introduces cyano in drug molecule and can change drug
The physicochemical characteristics of molecule enhances the interaction of drug molecule and target proteins, to improve drug effect；In addition, cyano is also
With good metabolic stability and as the bioelectronics isostere of the functional groups such as hydroxyl, carboxyl, these features make cyano
As the very important functional group of one kind in pharmaceutical chemistry research.30 kinds of cyano-containing drug listing it has been greater than at present, up to
More than 20 cyano-containing drug is being researched and developed.
Cyano or an important functional group in aromatic nitrile compounds can be converted into other by chemical reaction
Functional group forms other important organic compounds, such as: can obtain amides compound by hydrogenating reduction；Pass through hydrolysis
Available carboxylic acid compound；By restoring available primary amine compound or aromatic aldehyde compound；It is anti-by addition
Answer available tetrazole compound；Pass through the available carbonyl complex of nucleophilic addition.
In view of the peculiar property and important function of cyano, the synthesis of the compound of cyano-containing especially aromatic nitrile compounds
Receive the extensive concern of people.The method of traditional synthesis aromatic nitriles be Rosenmund-von Braun reaction and
Sandmeyer reaction certainly will will cause with much money since both methods requires the cuprous cyanide of equivalent as cyanylation agent
The pollution of category, and higher temperature (150~250 DEG C) is usually required in reaction, post-processing is cumbersome, to limit both
The utilization of method.It industrially prepares aryl nitrile compound and mainly passes through ammonia oxidation, but its reaction needs at high temperature under high pressure
It carries out, and uses big excess of ammonia, be confined to the cyanalation anti-of first benzene and its derivative and picoline and its derivative
It answers, to limit the utilization of this method.Therefore develop mild efficient cyanalation method, be allowed to meet the development of green chemical industry
Trend meets the needs that each related fields such as social production medicine, material rapidly develops, it appears especially urgent and needs.
Transition metal-catalyzed cross-coupling reaction is one of the effective method for constructing carbon-carbon bond, is urged using transition metal
The electrophilic reagent of change and the cross-coupling reaction of metal cyanides can be effectively formed aromatic nitrile compounds.1973
Takagi seminar report for the first time palladium chtalyst aryl iodide or aryl bromide with potassium cyanide coupling reaction
(Takagi,K.；Okamoto,T.；Sakakiba,Y.；Oka, S.Chem.Lett.1973,471), although in the paper only
Cyanalation reaction may be implemented in the substrate of limitation, but just because of the research work of this initiative, in subsequent decades,
Transition metal-catalyzed cyanalation reaction has obtained extensive research and development, and a series of cyanylation agent of low toxicities is developed
Come, such as: TMSCN, Zn (CN)2、K4Fe(CN)6, acetone cyanohydrin, NCTS etc..Aryl iodide and aryl bromide in such reaction
Due to its higher reactivity, it is often used as electrophilic reagent.The relatively wide aryl chlorine compound in source is due to C-Cl key
Bond energy is high, and activity is lower, is seldom used as electrophilic reagent in the research of early stage.But pass through Novel Ligands and catalyst system
Development, aryl chloride is also gradually applied among the cyanalation reaction of metal catalytic in recent years.However, being using halogenated hydrocarbons
There are clearly disadvantageous for electrophilic reagent: organohalogen compounds have certain harm to environment due to its own toxicity；Secondly aryl halide
Compound can generate halogen-containing by-product after carrying out coupling reaction；And aryl halide is less susceptible to directly obtain.Therefore, anxious
Some more environmentally-friendly, green electrophilic reagents need to be developed to synthesize aromatic nitrile compounds.
Pass through literature survey, it has been found that phenolic compound has from a wealth of sources, cheap, environmentally friendly etc. excellent
Point, is gradually applied in cross-coupling reaction.Simultaneously as the C-O key of phenol is broken difficulty, phenol is converted by phenolic compound
The function dough step by step of substrate may be implemented in analog derivative.Therefore it is anti-coupling to be applied to using phenol derivatives as electrophilic reagent
There is important research significance in answering.In recent years, still using the cyanalation reaction report of transition metal-catalyzed phenol derivatives
It is so less.1989, Widdowson seminar reported the trifluoromethane sulfonic acid aryl ester of nickel catalysis and the idol of potassium cyanide for the first time
Connection reaction, has synthesized a series of aromatic nitrile compounds.Subsequent Percec group has further developed the methanesulfonic acid of nickel catalysis
The coupling reaction of aryl ester and potassium cyanide.But need to use the potassium cyanide of hypertoxicity as cyanylation agent in the reaction, separately
Outside when there are when steric hindrance, reaction yield is lower at ortho position in substrate, such as when substrate is 2,4,6- trimethylphenyl triflates
When for substrate, the yield of reaction is 32%.(bibliography: Chambers, M.R.；Widdowson,
D.A.J.Chem.Soc.Perkin trans.I 1989,1366；Percec,V.；Bae,J.Y.；Hill,
D.H.J.Org.Chem.1995,60,6895.).Then, Neumeyer group and Fairfax group report the three of palladium chtalyst
The cyanalation reaction of methyl fluoride aryl sulfonate, the zinc cyanide for using toxicity relatively low in reaction is cyanogen source, but in reacting
Required temperature is up to 140 DEG C -200 DEG C.(bibliography: Zhang, A.；Neumeyer,J.L.Org.Lett.2003,5,
201；Srivastava,R.R.；Zych,A.J.；Jenkins,D.M.；Wang,H.J.；Chen,Z.J.；Fairfax,
D.J.Synthetic Communications,2007,37,431).Thereafter, Kwong seminar reports with the Asia of three hydrations
Potassium ferricyanate (K4[Fe(CN)6]·3H2It O is) cyanogen source, palladium chtalyst methanesulfonic acid aryl ester or p-methyl benzenesulfonic acid aryl ester are in mild item
Coupling reaction under part needs to be added the indoles with special electronic effect and steric effect of the group development in reaction
Phosphine ligands CM-phos, the ligand structure is special, and price is more expensive.(bibliography Yeung, P.Y.；So,C.M.；
Lau,C.P.；Kwong,F.Y.Angew.Chem.Int.Ed.2010,49,8918.).2016, Yamaguchi report with
Aminoacetonitriles is cyanogen source, and the cyanalation reaction of nickel catalytic amino formic acid aryl ester or aryl pivalate, reaction needs to use big
Steric hindrance rich electrical dcype or dcypt are ligand, and react required temperature and be up to 150 DEG C, to limit answering for the reaction
With (bibliography: Takise, R.；Itami,K.；Yamaguchi,J.Org.Lett.2016,18,4428.).In view of above-mentioned mistake
The cyanalation reaction for crossing the phenol derivatives of metal catalytic has its own limitation, such as needs special Phosphine ligands, complicated
Operate (pre-prepared catalyst) and post-processing, special catalyst precarsor and higher reaction temperature and longer reaction time
Deng.
Therefore, probe into and develop the more efficient, simple and direct, mild of cheap catalyst such as nickel and cheap ligand catalysis
The cyanalation method of sulfonates compounds then seems very urgent and needs, and will be realization aromatic nitriles or alkenyl nitrile
The commercial synthesis for closing object provides better application prospect.
Summary of the invention
The technical problem to be solved by the present invention is to the preparations in order to overcome existing aromatic nitriles or alkenyl nitrile compounds
The deficiencies of catalyst and ligand used in method are expensive, functional group compatibility is poor, substrate universality is bad, thus provide
A kind of preparation method of aromatic nitriles or alkenyl nitrile compounds.Preparation method of the invention can with cheap catalyst system,
It is simple and direct efficiently to realize the cyanalation of aromatic yl sulphonate, heteroaryl sulfonates or olefin sulfonic acid ester, but also there is good official
It can group's compatibility and substrate universality.
The present invention is to solve above-mentioned technical problem by following technical proposals.
The present invention provides a kind of preparation methods of aromatic nitrile compounds shown in formula I comprising following steps:
It, in a solvent, will be as shown in Formula II under the conditions of existing for nickel complex, metallic zinc and the additive under inert gas shielding
Aryl or heteroaryl sulfonates compounds and cyanylation agent carry out cross-coupling reaction as follows；Wherein, institute
The additive stated is 4-dimethylaminopyridine (DMAP), and the cyanylation agent is zinc cyanide；
In aromatic nitrile compounds shown in formula I and aryl or heteroaryl sulfonates compounds as shown in Formula II
In,
N is selected from any integer between 0- [M-1], and wherein M indicates the maximum substitution number on ring α, such as n can be 0,1
Or 2.
R1It may be the same or different, be each independently selected from halogen, C1-C6Straight or branched alkoxyl ,-CN ,-C (=
O)ORa、-NRbRc,-C (=O) Rd,-C (=O) NReRf、RgSubstituted C3-C10Aryl or heteroaryl, RhSubstituted C1-C6's
Linear or branched alkyl group；Wherein, Ra、Rb、Rc、Rd、Re、Rf、RgAnd RhIt is each independently selected from-H, halogen ,-OH ,-CN, C1-C4
Straight or branched alkoxyl and C1-C4One of linear or branched alkyl group or a variety of；Wherein, the halogen is preferably
Fluorine, chlorine, bromine or iodine；The C1-C4The preferred C of straight or branched alkoxyl1-C3Straight or branched alkoxyl, further it is excellent
It is selected as methoxyl group, ethyoxyl, propoxyl group or isopropoxy；The C1-C4Linear or branched alkyl group be preferably C1-C3It is straight
Chain or branched alkyl, further preferably methyl, ethyl, propyl or isopropyl.
Alternatively, the adjacent substituted R of any two1(when n >=2 when) atom on the ring α that is respectively connected with it is common
The carbocyclic ring or carbon heterocyclic of one with ring α and ring are constituted, the carbocyclic ring or carbon heterocyclic are 3-10 member ring, and the carbon heterocyclic contains
1-4 are selected from the hetero atom of O, N and S.
Work as R1When for halogen, the halogen is preferably fluorine, chlorine, bromine or iodine.
Work as R1For C1-C6Straight or branched alkoxyl when, the C1-C6Straight or branched alkoxyl be preferably C1-
C3Straight or branched alkoxyl, further preferably methoxyl group, ethyoxyl, propoxyl group or isopropoxy.
Work as R1For-C (=O) ORaWhen, RaPreferably C1-C4Linear or branched alkyl group, further preferably methyl, ethyl,
Propyl or isopropyl.
Work as R1For-NRbRcWhen, RbAnd RcIt is each independently preferably C1-C4Linear or branched alkyl group, further preferably
Methyl, ethyl, propyl or isopropyl.
Work as R1For-C (=O) RdWhen, RdPreferably C1-C4Linear or branched alkyl group, further preferably methyl, ethyl,
Propyl or isopropyl.
Work as R1For-C (=O) NReRfWhen, ReAnd RfIt is each independently preferably C1-C4Linear or branched alkyl group, further
Preferably methyl, ethyl, propyl or isopropyl.
Work as R1For RgSubstituted C3-C10Aryl or heteroaryl when, the C3-C10Aryl or heteroaryl be preferably benzene
Base or thienyl；
Work as R1For RhSubstituted C1-C6Linear or branched alkyl group when, the C1-C6Linear or branched alkyl group be preferably
C1-C3Linear or branched alkyl group, further preferably methyl, ethyl, propyl or isopropyl.
As the adjacent substituted R of any two1(when n >=2 when) the common structure of atom on the ring α that is respectively connected with it
At one and the carbocyclic ring or carbon heterocyclic of ring α and ring, the carbocyclic ring or carbon heterocyclic are preferably 3-5 member ring, and the carbon heterocyclic contains
There is 1 or 2 hetero atom for being selected from O, N and S.
When n is 1, R1Further preferably it is selected from methyl, normal-butyl, methoxyl group, amino, acetyl group, methoxycarbonyl, second
Epoxide carbonyl, cyano and phenyl.
When n is 2, R1It may be the same or different, be further preferably selected from methyl or methoxy each independently；Or two
R1The atom on ring α being respectively connected with it collectively forms dioxolyl.
- OS (=O)2R is the sulfonate structure that can be used as good leaving group described in the routine of this field, and wherein R is selected from
Halogen, C1-C6Linear or branched alkyl group, C1-C6Linear chain or branched chain halogenated alkyl or RiSubstituted phenyl, RiSelected from halogen
(such as fluorine, chlorine, bromine or iodine), C1-C6Linear or branched alkyl group (preferably C1-C3Linear or branched alkyl group, further preferably
Methyl, ethyl, propyl or isopropyl) or-NRjRk(RjAnd RkIt is each independently selected from C1-C4Linear or branched alkyl group, into one
Step is preferably methyl, ethyl, propyl or isopropyl).
When R is halogen, the halogen is preferably fluorine, chlorine, bromine or iodine.
When R is C1-C6Linear or branched alkyl group when, the C1-C6The preferred C of linear or branched alkyl group1-C3Straight chain
Or branched alkyl, further preferably methyl, ethyl, propyl or isopropyl.
When R is C1-C6Linear chain or branched chain halogenated alkyl when, the C1-C6Linear chain or branched chain halogenated alkyl be preferably
C1-C3Linear chain or branched chain halogenated alkyl, further preferably trifluoromethyl.
In the present invention ,-the OS (=O)2R is preferably following any structure: fluorosulfonyl (- SO2F), trifluoro methylsulfonyl
Base (- Tf), mesyl (- Ms), p-methylphenyl sulfonyl (- Ts) or amino-sulfonyl (- SO2NMe2)。
In the present invention, in aromatic nitrile compounds shown in formula I and aryl or heteroaryl sulfonates as shown in Formula II
In class compound, the ring α is aromatic ring or heteroaromatic.
Wherein, when the ring α is aromatic ring, the aromatic ring refers to any stable up to 6 originals in each ring
The monocycle of son or polycyclic carbocyclic ring, it is described it is polycyclic for two rings, tricyclic or Fourth Ring and ring structure, and wherein at least one ring is
Aromatic rings；When the aromatic ring is polycyclic and when wherein there is non-aromatic ring ,-OS (=O)2R and-CN connection are difference
It is carried out by " aromatic rings "；And n identical or different R1Connection and without any restriction.
Wherein, when the ring α is heteroaromatic, the heteroaromatic, which refers to, may be up to 6 in any stable each ring
The stabilization monocycle or polycyclic of atom, it is described it is polycyclic for two rings, tricyclic or Fourth Ring and ring structure, and wherein at least one
Ring is aromatic rings and is selected from the hetero atom of O, N and S containing 1-4.When the heteroaromatic be it is polycyclic and wherein exist it is non-aromatic
Fragrant ring or do not include hetero atom when ,-OS (=O)2R and-CN connection are by " containing heteroatomic fragrance respectively
What ring " carried out；And n identical or different-R1Connection and without any restriction.
In the present invention, the aromatic ring is preferably monocycle class aromatic rings or two ring class polycyclic aromatic rings, such as phenyl ring or naphthalene
Ring.
In the present invention, the heteroaromatic is preferably monocycle class pyridine ring or bicyclic class quinoline ring.
In the present invention, the aryl as shown in Formula II or heteroaryl sulfonates compounds and virtue shown in formula I
Fragrant nitrile compounds are more preferably following any pair of compound:
In the preparation method of the aromatic nitrile compounds shown in formula I, the cross-coupling reaction is in inertia
It is carried out under gas shield system, the inert protective gas can be one of nitrogen, helium, argon gas and neon or a variety of.
In the preparation method of the aromatic nitrile compounds shown in formula I, the dosage of the additive DMAP can
For used in the routine of this field；The present invention preferably described aryl as shown in Formula II or heteroaryl sulfonates compounds and DMAP
Molar ratio be 1:0.1-1:10, more preferably 1:1-1:1.5.
In the preparation method of the aromatic nitrile compounds shown in formula I, in addition to the additive DMAP, may be used also
Other additives are added, other described additives are quaternary ammonium salt and/or inorganic salts；Wherein, the preferred tetrem of the quaternary ammonium salt
Base ammonium iodide；One or more, more preferable potassium iodide in the preferred sodium iodide of the inorganic salts, potassium iodide and lithium iodide.
In the preparation method of the aromatic nitrile compounds shown in formula I, when in the reaction system also include season
When ammonium salt and/or inorganic salts, the dosage of the quaternary ammonium salt and/or inorganic salts can be for used in the routine of this field；The present invention is preferred
The molar ratio of the aryl as shown in Formula II or heteroaryl sulfonates compounds and the quaternary ammonium salt and/or inorganic salts
For 1:0.1-1:10, more preferably 1:0.5-1:1.
In the preparation method of the aromatic nitrile compounds shown in formula I, the dosage of the metallic zinc can be this
Used in the such reaction routine in field；The preferably described aryl as shown in Formula II of the present invention or heteroaryl sulfonates compounds with
The molar ratio of the metallic zinc is 1:0.01-1:10, more preferably 1:0.1-1:1, further preferably 1:0.2-1:0.4.
In the preparation method of the aromatic nitrile compounds shown in formula I, the nickel complex can be this field
Used in such cross-coupling reaction routine, the routinely applicable nickel cocatalyst well known in the art that can be prepared
The metal complex form participation that ligand is routinely applicable in it is reacted, and also no longer can separately add other ligands at this time；It can also be by this
Nickel cocatalyst routinely applicable known to field and its routinely applicable ligand carries out after complexed in situ again in the reaction system
Participate in reaction.The preferably described nickel complex of the present invention is NiBr2(PPh3)2And/or NiCl2(dppf)；Or, the present invention is preferred
The nickel cocatalyst is selected from Ni (cod)2、NiCl2、NiBr2、NiI2、NiBr2(diglyme)、NiCl2(glyme)、
NiBr2(DME)、NiF2And NiCl2·6H2One of O or a variety of；Such as NiBr2(DME)、NiI2And NiCl2·6H2In O
It is one or more.
In the preparation method of the aromatic nitrile compounds shown in formula I, the dosage of the nickel complex can be
Used in such reaction routine of this field；The present invention preferably described aryl as shown in Formula II or heteroaryl sulfonates compounds
Molar ratio with the nickel complex is 1:0.01-1:1, more preferable 1:0.02-1:0.50, further preferred 1:0.05-1:
0.10。
In the preparation method of the aromatic nitrile compounds shown in formula I, as also included institute in the reaction system
The routine stated is applicable in ligand, can be the conventional ligands in such cross-coupling reaction of this field suitable for Raney nickel, optional
From triphenylphosphine (PPh3), triethyl phosphine, tributylphosphine (TBUP), tricyclohexyl phosphine (TCHP), double diphenylphosphine methane
(dppm), dimethylphenylphosphine (PMe2Ph), diphenyl methyl phosphine (PMePh2), bis- (diphenyl phosphine) ethane (dppe) of 1,2-, 1,3-
Bis- (diphenylphosphine) propane (dppp), bis- (diphenylphosphine) butane (dppb) of 1,4-, bis- (diphenylphosphine) ferrocene of 1,1'-
(dppf), 9,9- dimethyl -4,5- double diphenylphosphine xanthenes (xantphos), 4,5- bis- (di-t-butyl phosphine) -9,9- diformazan
Base xanthene (t) and one in 3- (dicyclohexyl phosphino-) -1- methyl -2- phenyl -1H- indoles (CM-phos) Bu-xantphos
Kind is a variety of, more preferably double diphenylphosphine methane (dppm), diphenyl methyl phosphine (PMePh2), bis- (diphenyl phosphine) ethane of 1,2-
(dppe), bis- (diphenylphosphine) propane (dppp) of 1,3-, bis- (diphenylphosphine) butane (dppb) of 1,4-, the bis- (diphenyl of 1,1'-
Phosphine) one of ferrocene (dppf) and the double diphenylphosphine xanthenes (xantphos) of 9,9- dimethyl -4,5- or a variety of；Such as
One of bis- (diphenylphosphine) ferrocene of diphenyl methyl phosphine, 1,1'- and the double diphenylphosphine xanthenes of 9,9- dimethyl -4,5-
Or it is a variety of.
In the preparation method of the aromatic nitrile compounds shown in formula I, as also included institute in the reaction system
The routine stated is applicable in ligand, and the molar ratio of the nickel cocatalyst and the ligand can be such cross-coupling of this field
It reacts used in routine.Preferred molar ratio of the present invention is 1:1~1:10, more preferable 1:1~1:5, further preferred 1:1.2.
In the preparation method of the aromatic nitrile compounds shown in formula I, the aryl as shown in Formula II or
Heteroaryl sulfonates compounds such can react conventional molar ratio for this field with the molar ratio of the cyanylation agent；
The present invention preferred 1:0.1-1:10, more preferable 1:0.5-1:2, further preferred 1:0.6-1:1.2, such as 1:0.8.
In the preparation method of the aromatic nitrile compounds shown in formula I, the solvent can for this field such
Used in cross-coupling reaction routine, it is not involved in reaction；Preferred aromatic hydrocarbons class solvent of the present invention, ether solvent, halogenated hydrocarbon are molten
One of agent, nitrile solvents, amide solvent and sulfoxide type solvents are a variety of；The preferred benzene of the aromatic hydrocarbon solvent, toluene
With one of dimethylbenzene or a variety of；The preferred ether of the ether solvent, Isosorbide-5-Nitrae-one of dioxane and tetrahydrofuran
Or it is a variety of；The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent；The preferred methylene chloride of the chlorinated hydrocarbon solvent, dichloro
One of ethane and chloroform are a variety of；The preferred acetonitrile of the nitrile solvents；The preferred N of the amide solvent, N- diformazan
One of base formamide, DMAC N,N' dimethyl acetamide (DMA) and hexamethyl phosphoramide are a variety of；The sulfoxide type solvents are excellent
Select dimethyl sulfoxide.One of the more preferable acetonitrile of the solvent, N,N-dimethylformamide and DMAC N,N' dimethyl acetamide
Or it is a variety of.
In the preparation method of the aromatic nitrile compounds shown in formula I, the dosage of the solvent can be ability
Used in such cross-coupling reaction routine of domain；The present invention preferably described aryl as shown in Formula II or heteroaryl sulfonates class
The molal volume ratio for closing object and the solvent is 0.01mmol/mL-1mmol/mL, more preferable 0.1mmol/mL-0.5mmol/
mL。
In the preparation method of the aromatic nitrile compounds shown in formula I, the reaction of the cross-coupling reaction
Temperature can be for used in such cross-coupling reaction routine of this field；It can be -100 DEG C -500 DEG C, preferably 0 DEG C -150 in the present invention
DEG C, more preferable 50 DEG C -100 DEG C, further preferred 60 DEG C -80 DEG C.
In the preparation method of the aromatic nitrile compounds shown in formula I, the reaction of the cross-coupling reaction
Process can be carried out using routine monitoring method (such as TLC, HPLC or NMR) used in such cross-coupling reaction in this field
Monitoring is reaction when generally with described, the aryl as shown in Formula II or heteroaryl sulfonates compounds disappear or no longer react
Terminal.
In the preparation method of the aromatic nitrile compounds shown in formula I, the reaction of the cross-coupling reaction
Time can be for used in such cross-coupling reaction routine of this field；Preferred 0.1-200h in the present invention, further preferred 3-12h.
In the preparation method of the aromatic nitrile compounds shown in formula I, the preparation method is in the friendship
After pitching coupling reaction, preferably may also include following post-processing step: after reaction, filtering removes solvent, column chromatography point
From target compound is obtained, the pillar layer separation can be using the conventional method of the generic operation in this field.Eluant, eluent is excellent
Select the mixed solvent of alkane solvents and esters solvent.Wherein, the volume of the alkane solvents and the esters solvent
Than preferred 100:1-1:1；The preferred petroleum ether of the alkane solvents；The esters solvent ethyl acetate.
The preparation method of the present invention also provides a kind of alkenyl nitrile compounds as shown in formula III comprising following step
It is rapid: under inert gas protection, in a solvent, will be as shown in IV under the conditions of existing for nickel complex, metallic zinc and the additive
Olefin sulfonic acid ester type compound and cyanylation agent carry out cross-coupling reaction as follows；Wherein, described to add
Adding agent is 4-dimethylaminopyridine (DMAP)；The cyanylation agent is zinc cyanide；
Wherein ,-OS (=O)2R is the sulfonate structure that can be used as good leaving group described in the routine of this field, is determined
Justice is as described above, it may be assumed that R is selected from halogen, C1-C6Linear or branched alkyl group, C1-C6Linear chain or branched chain halogenated alkyl or RiIt takes
The phenyl in generation, RiSelected from halogen (such as fluorine, chlorine, bromine or iodine), C1-C6Linear or branched alkyl group (preferably C1-C3Linear chain or branched chain
Alkyl, further preferably methyl, ethyl, propyl or isopropyl) or-NRjRk(RjAnd RkIt is each independently selected from C1-C4It is straight
Chain or branched alkyl, further preferably methyl, ethyl, propyl or isopropyl).
When R is halogen, the halogen is preferably fluorine, chlorine, bromine or iodine.
When R is C1-C6Linear or branched alkyl group when, the C1-C6The preferred C of linear or branched alkyl group1-C3Straight chain
Or branched alkyl, further preferably methyl, ethyl, propyl or isopropyl.
When R is C1-C6Linear chain or branched chain halogenated alkyl when, the C1-C6Linear chain or branched chain halogenated alkyl be preferably
C1-C3Linear chain or branched chain halogenated alkyl, further preferably trifluoromethyl.
In the present invention ,-the OS (=O)2R is preferably following any structure: fluorosulfonyl (- SO2F), trifluoro methylsulfonyl
Base (- Tf), mesyl (- Ms), p-methylphenyl sulfonyl (- Ts) or amino-sulfonyl (- SO2NMe2)。
In alkenyl nitrile compounds and the olefin sulfonic acid ester type compound as shown in formula IV as shown in formula III, R2、R3
And R4It is each independently selected from-H ,-(CH2)x-RmSubstituted C3-C10Aryl or heteroaryl or RnSubstituted C1-C6Straight chain
Or branched alkyl；Wherein, RmAnd RnIt is each independently selected from-H, halogen ,-OH ,-CN, C1-C4Straight or branched alkoxyl and
C1-C4One of linear or branched alkyl group or a variety of；Wherein, the halogen is preferably fluorine, chlorine, bromine or iodine；Described
C1-C4The preferred C of straight or branched alkoxyl1-C3Straight or branched alkoxyl, be further methoxyl group, ethyoxyl, the third oxygen
Base or isopropoxy；The C1-C4Linear or branched alkyl group be preferably C1-C3Linear or branched alkyl group, further preferably
For methyl, ethyl, propyl or isopropyl；X is selected from any integer between 0-4, such as 0,1,2 or 3.
Wherein, described-(CH2)x-RmSubstituted C3-C10Aryl or heteroaryl in, the C3-C10Aryl or miscellaneous
The preferred C of aryl6-C10Aryl, such as phenyl or naphthyl.
Wherein, the RnSubstituted C1-C6Linear or branched alkyl group in, the C1-C6Linear or branched alkyl group
Preferably C1-C3Linear or branched alkyl group, further preferably methyl, ethyl, propyl or isopropyl.
Alternatively, R2With R3Or R2With R4The monocycle or polycyclic carbocyclic ring or carbon heterocyclic of a 5-10 member are collectively formed, it is described
Carbon heterocyclic contains the 1-4 hetero atoms for being selected from O, N and S；The monocycle of the 5-10 member or polycyclic carbocyclic ring or carbon heterocyclic can be full
And/or semi-saturation ring；And it can be further by RnReplace.
Wherein, the monocycle of the 5-10 member or the preferred monocycle of polycyclic carbocyclic ring or bicyclic carbocyclic, further preferably hexamethylene
Alkene or benzo cyclohexene.
In the present invention, alkenyl nitrile compounds and the olefin sulfonic acid ester type compound as shown in formula IV as shown in formula III
In, it can be Z-type and/or E type, be not necessarily to any restriction.
In the present invention, olefin sulfonic acid ester type compound and the alkenyl nitrile as shown in formula III as shown in formula IV
Compound is more preferably following any pair of compound:
In the present invention, such as it is not particularly limited, in addition to substrate used is different, the alkenyl nitrile as shown in formula III
The each response parameter and condition used in the preparation method of compound is as described above, it may be assumed that
In the preparation method of alkenyl nitrile compounds as shown in formula III, the cross-coupling reaction is lazy
Property gas shield system under carry out, the inert protective gas can be one of nitrogen, helium, argon gas and neon or more
Kind.
In the preparation method of alkenyl nitrile compounds as shown in formula III, the dosage of the additive DMAP
It can be for used in the routine of this field；Preferably described mole of olefin sulfonic acid ester type compound and DMAP as shown in formula IV of the present invention
Than for 1:0.1-1:10, more preferably 1:1-1:1.5.
In the preparation method of alkenyl nitrile compounds as shown in formula III, in addition to the additive DMAP, also
Other additives can be added, other described additives are quaternary ammonium salt and/or inorganic salts；Wherein, the quaternary ammonium salt preferably four
Ethyl phosphonium iodide ammonium；One or more, more preferable potassium iodide in the preferred sodium iodide of the inorganic salts, potassium iodide and lithium iodide.
In the preparation method of alkenyl nitrile compounds as shown in formula III, when also including in the reaction system
When quaternary ammonium salt and/or inorganic salts, the dosage of the quaternary ammonium salt and/or inorganic salts can be for used in the routine of this field；The present invention is excellent
The molar ratio of the choosing olefin sulfonic acid ester type compound as shown in formula IV and the quaternary ammonium salt and/or inorganic salts is 1:
0.1-1:10, more preferably 1:0.5-1:1.
In the preparation method of alkenyl nitrile compounds as shown in formula III, the dosage of the metallic zinc can be
Used in the such reaction routine in this field；The preferably described olefin sulfonic acid ester type compound shown in formula IV of the present invention is with as described in
The molar ratio of metallic zinc is 1:0.01-1:10, more preferably 1:0.1-1:1, further preferably 1:0.2-1:0.4.
In the preparation method of alkenyl nitrile compounds as shown in formula III, the nickel complex can be ability
Used in such cross-coupling reaction routine of domain, the nickel precursor well known in the art being routinely applicable in that can be prepared is catalyzed
The metal complex form participation that agent is routinely applicable in ligand with it is reacted, and also no longer can separately add other ligands at this time；It can also incite somebody to action
After the nickel cocatalyst well known in the art being routinely applicable in and the applicable ligand of its routine carry out complexed in situ in the reaction system
It participates in reacting again.The preferably described nickel complex of the present invention is NiBr2(PPh3)2And/or NiCl2(dppf)；Or, the present invention is excellent
The choosing nickel cocatalyst is selected from Ni (cod)2、NiCl2、NiBr2、NiI2、NiBr2(diglyme)、NiCl2(glyme)、
NiBr2(DME)、NiF2And NiCl2·6H2One of O or a variety of；Such as NiBr2(DME)、NiI2And NiCl2·6H2In O
It is one or more.
In the preparation method of alkenyl nitrile compounds as shown in formula III, the dosage of the nickel complex can
For used in such reaction routine of this field；The preferably described olefin sulfonic acid ester type compound as shown in formula IV of the present invention with it is described
Nickel complex molar ratio be 1:0.01-1:1, more preferable 1:0.02-1:0.50, further preferred 1:0.05-1:0.10.
In the preparation method of alkenyl nitrile compounds as shown in formula III, as also included in the reaction system
The routine is applicable in ligand, can be the conventional ligands for being suitable for Raney nickel in such cross-coupling reaction of this field, can
Selected from triphenylphosphine (PPh3), triethyl phosphine, tributylphosphine (TBUP), tricyclohexyl phosphine (TCHP), double diphenylphosphine methane
(dppm), dimethylphenylphosphine (PMe2Ph), diphenyl methyl phosphine (PMePh2), bis- (diphenyl phosphine) ethane (dppe) of 1,2-, 1,3-
Bis- (diphenylphosphine) propane (dppp), bis- (diphenylphosphine) butane (dppb) of 1,4-, bis- (diphenylphosphine) ferrocene of 1,1'-
(dppf), 9,9- dimethyl -4,5- double diphenylphosphine xanthenes (xantphos), 4,5- bis- (di-t-butyl phosphine) -9,9- diformazan
Base xanthene (t) and one in 3- (dicyclohexyl phosphino-) -1- methyl -2- phenyl -1H- indoles (CM-phos) Bu-xantphos
Kind is a variety of, more preferably double diphenylphosphine methane (dppm), diphenyl methyl phosphine (PMePh2), bis- (diphenyl phosphine) ethane of 1,2-
(dppe), bis- (diphenylphosphine) propane (dppp) of 1,3-, bis- (diphenylphosphine) butane (dppb) of 1,4-, the bis- (diphenyl of 1,1'-
Phosphine) one of ferrocene (dppf) and the double diphenylphosphine xanthenes (xantphos) of 9,9- dimethyl -4,5- or a variety of；Such as
One of bis- (diphenylphosphine) ferrocene of diphenyl methyl phosphine, 1,1'- and the double diphenylphosphine xanthenes of 9,9- dimethyl -4,5-
Or it is a variety of.
In the preparation method of alkenyl nitrile compounds as shown in formula III, as also included in the reaction system
The routine is applicable in ligand, and the molar ratio of the nickel cocatalyst and the ligand such can intersect occasionally for this field
Used in connection reaction routine.Preferred molar ratio of the present invention is 1:1~1:10, more preferable 1:1~1:5, further preferred 1:1.2.
In the preparation method of alkenyl nitrile compounds as shown in formula III, the alkenyl as shown in formula IV
Sulfonates compounds such can react conventional molar ratio for this field with the molar ratio of the cyanylation agent；The present invention
It is preferred that 1:0.1-1:10, more preferable 1:0.5-1:2, further preferred 1:0.6-1:1.2, such as 1:0.8.
In the preparation method of alkenyl nitrile compounds as shown in formula III, the solvent can be somebody's turn to do for this field
Used in class cross-coupling reaction routine, it is not involved in reaction；Preferred aromatic hydrocarbons class solvent of the present invention, ether solvent, halogenated hydrocarbon
One of solvent, nitrile solvents, amide solvent and sulfoxide type solvents are a variety of；The preferred benzene of the aromatic hydrocarbon solvent, first
One of benzene and dimethylbenzene are a variety of；One in the preferred ether of the ether solvent, Isosorbide-5-Nitrae-dioxane and tetrahydrofuran
Kind is a variety of；The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent；The preferred methylene chloride of the chlorinated hydrocarbon solvent, two
One of chloroethanes and chloroform are a variety of；The preferred acetonitrile of the nitrile solvents；The amide solvent preferred N, N- bis-
One of methylformamide, DMAC N,N' dimethyl acetamide (DMA) and hexamethyl phosphoramide are a variety of；The sulfoxide type solvents
It is preferred that dimethyl sulfoxide.One in the more preferable acetonitrile of the solvent, N,N-dimethylformamide and DMAC N,N' dimethyl acetamide
Kind is a variety of.
In the preparation method of alkenyl nitrile compounds as shown in formula III, the dosage of the solvent can be this
Used in such cross-coupling reaction routine of field；The preferably described olefin sulfonic acid ester type compound as shown in formula IV of the present invention with
The molal volume ratio of the solvent is 0.01mmol/mL-1mmol/mL, more preferable 0.1mmol/mL-0.5mmol/mL.
In the preparation method of alkenyl nitrile compounds as shown in formula III, the cross-coupling reaction it is anti-
Answer temperature can be for used in such cross-coupling reaction routine of this field；It can be -100 DEG C -500 DEG C, preferably 0 DEG C -150 in the present invention
DEG C, more preferable 50 DEG C -100 DEG C, further preferred 60 DEG C -80 DEG C.
In the preparation method of alkenyl nitrile compounds as shown in formula III, the cross-coupling reaction it is anti-
Answer process can using routine monitoring method (such as TLC, HPLC or NMR) used in such cross-coupling reaction in this field into
Row monitoring, as reaction end when generally the olefin sulfonic acid ester type compound as shown in formula IV disappears or no longer reacts using described.
In the preparation method of alkenyl nitrile compounds as shown in formula III, the cross-coupling reaction it is anti-
It can be for used in such cross-coupling reaction routine of this field between seasonable；Preferred 0.1-200h in the present invention, further preferred 3-
12h。
In the preparation method of alkenyl nitrile compounds as shown in formula III, the preparation method is described
After cross-coupling reaction, preferably may also include following post-processing step: after reaction, filtering removes solvent, column chromatography
Isolated target compound, the pillar layer separation can be using the conventional methods of the generic operation in this field.Eluant, eluent
It is preferred that the mixed solvent of alkane solvents and esters solvent.Wherein, the body of the alkane solvents and the esters solvent
Product is than preferred 100:1-1:1；The preferred petroleum ether of the alkane solvents；The esters solvent ethyl acetate.
The present invention further additionally provides a kind of aromatic nitrile compounds or the alkenyl as shown in formula III shown in formula I
Nitrile compounds,
Wherein, each substituent group defines as described above.
Specifically, the present invention also provides a kind of aromatic nitriles as shown in following structures or alkenyl nitrile compounds:
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: the present invention realizes aryl sulfonic acid using catalyst system simple and easy to get
The cyanalation reaction of ester, heteroaryl sulfonates or olefin sulfonic acid ester, with simple to operation, reaction is efficient, mild condition, functional group
The advantages that compatibility and substrate universality are good, to realize that the commercial synthesis of aromatic nitriles or alkenyl nitrile compounds provides preferably
Application prospect and use value.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Preparation example 1:
General preparation process: it is sequentially added in round-bottomed bottle to iodophenol (1equiv), boric acid (1.2equiv), 5%Pd/
CaCO3(1.5mol%), K2CO3(2equiv), EtOH and water dissolution are heated to 80 DEG C of reflux, TLC detection reaction.Restore to room
Temperature, diatomite are filtered to remove precipitating, saturated salt solution quenching reaction, ethyl acetate extraction, organic phase washing, saturated salt solution
It washes, anhydrous magnesium sulfate isolates and purifies after drying, filtering concentration.
Silica gel column chromatography, eluent: petrol ether/ethyl acetate/methylene chloride=8:1:1 to absolute dichloromethane, product are
White solid 1.81g, yield 91%.M.p=81.0-82.9 DEG C of1H NMR(400MHz,CDCl3):δ3.85(s,3H),5.47
(brs, 1H), 6.84-6.89 (m, 3H), 7.07 (s, 1H), 7.12 (d, J=7.6Hz, 1H), 7.32 (dd, J=8.0Hz, 1H),
7.45 (d, J=7.6Hz, 2H)13C NMR(100MHz,CDCl3):δ55.30,112.07,112.48,115.62,119.33,
128.39,129.72,133.71,142.27,155.17,159.76.IR(neat):3499,3419,3362,1597,1583,
1520,1488,1412,1265,1213,1175,1107,1016,860,831,820,781,688.HRMS(ESI)calcd
for C13H13O2[M+H]+:201.0910,found 201.0910.
Silica gel column chromatography, eluent: petrol ether/ethyl acetate/methylene chloride=6:1:1 to petroleum ether/methylene chloride=
1:1, afterwards with methylene chloride/n-hexane recrystallization, product is white solid 1.09g, yield 62%.M.p=172.4-174.2
℃.1H NMR(400MHz,DMSO-d6): δ 6.81 (d, J=7.6Hz, 2H), 7.44-7.45 (m, 1H), 7.53-7.55 (m,
3H),7.61(s,1H),9.50(s,1H).13C NMR(100MHz,DMSO-d6):δ115.61,118.52,125.98,
126.42,126.66,127.29,141.62,156.72.IR(neat):3386,3096,3029,1597,1532,1500,
1444,1372,1250,1199,1181,1110,1009,863,833,800,774,714cm-1.HRMS(EI)calcd for
C10H8OS[M]+:176.0296,found 176.0295.
Preparation example 2:
Phenol (1equiv) is dissolved in ethyl acetate in round-bottomed bottle, and Et is added under ice-water bath3N (2equiv), MsCl
(1.3equiv) adds recession and removes ice-water bath, react at room temperature, and TLC detects fully reacting.Water quenching reaction, acetic acid is added
Ethyl ester extraction, organic phase washing, anhydrous magnesium sulfate is dry, and silica gel filtering isolates and purifies after filtrate concentration.
Silica gel column chromatography, eluent: petrol ether/ethyl acetate=4:1, product are light yellow liquid, yield 98%.1H
NMR(400MHz,CDCl3): δ 0.93 (t, J=7.2Hz, 3H), 1.32-1.38 (m, 2H), 1.55-1.63 (m, 2H), 2.61
(t, J=7.6Hz, 2H), 3.11 (s, 3H), 7.17-7.26 (m, 4H)13C NMR(100MHz,CDCl3):δ13.83,22.21,
33.44,34.94,37.09,121.63,129.79,142.28,147.18.IR(neat):3029,2957,2932,2860,
1503,1365,1330,1197,1173,1147,1113,1018,968,865,841,814,776,740,681.HRMS(ESI)
calcd for C11H20NO3S[M+NH4]+:246.1158,found 246.1157.
Silica gel column chromatography, eluent: petrol ether/ethyl acetate/methylene chloride=4:1:1, product are white solid, yield
94%.M.p=53.8-55.1 DEG C of1H NMR(400MHz,CDCl3):δ2.35(s,3H),3.14(s,3H),3.86(s,3H),
6.74-6.77 (m, 1H), 6.81 (d, J=1.6Hz, 1H), 7.16 (d, J=8.4Hz, 1H)13C NMR(100MHz,CDCl3):
δ21.35,37.93,55.75,113.56,121.38,123.95,136.02,138.48,150.81.IR(neat):3037,
3013,2933,2843,1602,1505,1473,1415,1356,1290,1196,1174,1145,1110,1035,966,
850,812,786,684.HRMS(ESI)calcd for C9H16NO4S[M+NH4]+:234.0794,found 234.0792.
Methylene chloride/n-hexane recrystallization, product is white solid, yield 89%.M.p=148.6-149.7 DEG C of1H
NMR(400MHz,CDCl3): δ 2.39 (s, 3H), 3.15 (s, 3H), 7.24 (d, J=7.6Hz, 2H), 7.32 (d, J=8.4Hz,
2H), 7.44 (d, J=7.2Hz, 2H), 7.59 (d, J=7.6Hz, 2H)13C NMR(100MHz,CDCl3):21.04,37.25,
122.18,126.89,128.38,129.57,136.75,137.58,140.50,148.31.IR(neat):3039,3026,
2944,1611,1491,1360,1334,1173,1151,973,964,867,852,811,788,720,655.HRMS(ESI)
calcd for C14H18NO3S[M+NH4]+:280.1002,found 280.0998.
Methylene chloride/n-hexane recrystallization, product is white solid, yield 95%.M.p=83.4-85.0 DEG C of1H NMR
(400MHz,CDCl3,Me4Si): δ 3.16 (s, 3H), 3.86 (s, 3H), 6.91 (d, J=8.4Hz, 1H), 7.07 (s, 1H),
7.13 (d, J=7.6Hz, 1H), 7.33-7.38 (m, 3H), 7.59-7.61 (m, 2H)13C NMR(100MHz,CDCl3,
Me4Si):37.31,55,25,112.92,113.01,119.54,122.20,128.67,129.89,140.42,141.15,
148.59,159.94.IR(neat):2962,2938,2838,1608,1576,1482,1356,1333,1299,1215,
1171,1147,1056,972,963,862,838,793,735,721,696.HRMS(ESI)calcd for C14H18NO4S[M+
NH4]+:296.0951,found 296.0948.
Silica gel column chromatography, methylene chloride/n-hexane recrystallization, product is white solid, yield 95%.M.p=120.8-
122.2℃.1H NMR(400MHz,DMSO-d6): δ 7.27-7.31 (m, 2H), 7.45 (d, J=8.0Hz, 2H), 7.69-7.75
(m,4H).13C NMR(100MHz,DMSO-d6):δ37.40,115.79(2JC-F=21.3Hz), 122.73,128.33,
128.83(3JC-F=7.5Hz), 135.38 (4JC-F=3.8Hz), 138.31,148.56,162.08 (1JC-F=242.9Hz)19F
NMR(376.1MHz,DMSO-d6):δ-114.95.IR(neat):3062,3029,2944,1735,1599,1491,1370,
1336,1254,1210,1182,1157,1115,1016,1006,968,945,864,825,789,739,719,653.HRMS
(ESI)calcd for C13H15FNO3S[M+NH4]+:284.0751,found 284.0750.
Methylene chloride/n-hexane recrystallization, product is white solid, yield 84%.M.p=160.8-162.2 DEG C of1H
NMR(400MHz,DMSO-d6): δ 3.41 (s, 3H), 7.40 (d, J=8.0Hz, 2H), 7.57 (d, J=3.6Hz, 1H), 7.65
(d, J=2.0Hz, 1H), 7.82 (d, J=8.0Hz, 2H), 7.91 (s, 1H)13C NMR(100MHz,DMSO-d6):37.36,
121.72,122.70,126.22,127.36,127.66,134.34,140.15,148.06.IR(neat):3096,3037,
3024,2941,1600,1530,1495,11372,1327,1203,1182,1155,1107,1011,970,863,850,819,
792,780,729,709.HRMS(ESI)calcd for C11H14NO3S2[M+NH4]+:272.0410,found272.0410.
Preparation example 3:
Aldehyde radical phenol (1.22g, 10mmol) is dissolved in the ethyl acetate of 30mL in round-bottomed bottle, Et is added at 0 DEG C3N
(2.8mL, 20mmol), MsCl (1.0mL, 13mmol) add recession and remove ice-water bath, react at room temperature, and TLC detection has been reacted
Entirely.Water quenching reaction is added, ethyl acetate extraction, organic phase washing, saturated common salt washing, anhydrous magnesium sulfate is dry, silica gel mistake
Filter carries out next step reaction after filtrate concentration.
Upper step product is dissolved in 20mL MeOH and 20mL DCM, NaBH is added portionwise4(491.8mg, 13mmol), adds
It is reacted at room temperature after complete, TLC detects fully reacting.Saturated ammonium chloride quenching reaction, DCM extraction is added, organic phase washing is satisfied
It is washed with salt, anhydrous sodium sulfate dries, filters concentration, and silica gel column chromatography, eluent: petrol ether/ethyl acetate=4:1 is divided
From obtaining colourless liquid 1.899g, yield 95%.1H NMR(400MHz,CDCl3):δ1.05(br,1H),3.11(s,3H),
4.65 (s, 2H), 7.24 (d, J=7.6Hz, 2H), 7.38 (d, J=8.0Hz, 2H)13C NMR(100MHz,CDCl3):δ
37.21,64.02,121.93,128.31,140.26,148.24.IR(neat):3561,3383,3024,2939,2871,
1603,1504,1412,1358,1196,1170,1144,1015,969,865,838,812,773,678.HRMS(ESI)
calcd for C8H14NO4S[M+NH4]+:220.0637,found220.0638.
Preparation example 4:
Argon gas protection under, into the Schlenk reaction tube of standard be added 4-phenylcyclohexan-1-one (1.39g,
8 and THF (30mL).Reaction solution is cooled to -15 DEG C, be added at one time KHMDS (0.5M in toluene, 17.6mL,
8.8mmol), in -15 DEG C of stirring 1h after adding.Then in -15 DEG C it is upper disposable be added 4- toluenesulfonic acid acid anhydride (2.87g,
8.8mmol).In -15 DEG C of stirring 0.5h after adding, then restores to reacting at room temperature, after TLC detects fully reacting, add saturation
NaHCO3Quenching reaction, EA extraction, organic phase are washed with water, and saturated common salt washing, anhydrous sodium sulfate dries, filters, filtrate concentration
Rear pillar chromatography.Eluent: petrol ether/ethyl acetate=15:1 obtains white solid, and ethyl acetate/hexane recrystallization obtains white
Color solid 841.6mg, yield 32%.M.p.:100.8-101.5℃.1H NMR(400MHz,CDCl3):δ1.80-1.87(m,
1H),1.93-1.96(m,1H),2.16-2.22(m,2H),2.26-2.33(m,2H),2.47(s,3H),2.71-2.76(m,
1H), 7.17-7.23 (m, 3H), 7.26-7.32 (m, 2H), 7.36 (d, J=8.0Hz, 2H), 7.83 (d, J=7.2Hz, 2H)
.13C NMR(100MHz,CDCl3):δ21.67,27.85,29.65,31.57,38.87,116.4,126.35,126.71,
128.20,128.44,129.66,133.48,144.92,145.18,147.94.IR(neat):3060,3029,2920,
2892,2840,1735,1681,1593,1493,1371,1290,1190,1174,1081,1036,891,853,815,763,
743,696,688,675.HRMS(ESI)calcd for C19H24NO3S[M+NH4]+:346.1471,found346.1466.
Preparation example 5:
Argon gas protection under, into the Schlenk reaction tube of standard be added 1-acetonaphthone (1.36g, 8mmol) and
THF(24mL).Reaction solution is cooled to -20 DEG C, and 1.0M is added dropwisetThe THF (11mL) of BuOK (1.27g, 11.2mmol) is molten
Liquid, 10min are added.In 0 DEG C of stirring 1.5h after adding.- 20 DEG C are subsequently cooled to, 4- toluenesulfonic acid acid anhydride is added at one time
(3.13g,9.6mmol).In -20 DEG C of stirrings 1h, 0 DEG C of stirring 6h after adding, then restore to reacting at room temperature, TLC detection is reacted
After completely, add saturation NaHCO3Quenching reaction, EA extraction, organic phase are washed with water, and saturated common salt washing, anhydrous sodium sulfate is dry,
Rear pillar chromatography is concentrated in filtering, filtrate.Eluent: petrol ether/ethyl acetate=20:1 obtains yellow liquid 1.77g, yield
54%.1H NMR(400MHz,CDCl3): δ 2.24 (s, 3H), 5.25 (d, J=1.6Hz, 1H), 5.54 (d, J=2.0Hz, 1H),
6.90 (d, J=8.0Hz, 2H), 7.28-7.32 (t, J=7.2Hz, 1H), 7.37 (d, J=7.2Hz, 1H), 7.41-7.45 (m,
3H),7.71-7.75(m,2H),8.00-8.02(m,1H).13C NMR(100MHz,CDCl3):δ21.36,108.94,
124.62,125.31,125.92,126.56,127.87,127.94,127.99,128.84,129.81,130.39,131.42,
132.82,133.17,144.39,152.90.IR(neat):3117,3052,2944,1655,1590,1505,1451,1364,
1234,1190,1171,1125,1089,922,900,851,798,777,731,682,655.HRMS(ESI)calcd for
C19H20NO3S[M+NH4]+:342.1158,found 342.1151.
1 compound of embodiment (1a)
It is being full of N2Glove box in, NiCl is sequentially added into the bottle with sealing plug2·6H2O(5.9mg,
0.025mmol), dppf (16.6mg, 0.03mmol), Zn (6.5mg, 0.1mmol), Zn (CN)2(47.0mg,0.4mmol),
DMAP (91.6mg, 0.75mmol), 4- acetylphenyl methanesulfonates (107.1mg, 0.5mmol), CH3CN(5mL).It covers
Son moves back out glove box, is placed directly in 80 DEG C of oil baths and heats reaction, room temperature is cooled to after 12h, silica gel filters after TLC detection, second
Acetoacetic ester is washed, concentration rear pillar chromatography.Eluent: petrol ether/ethyl acetate=5:1, product are white solid 67.8mg, yield
93%,1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3): δ 2.67 (s, 3H), 7.80 (d, J=8.4Hz, 2H),
8.07 (d, J=8.4Hz, 2H)13C NMR(100MHz,CDCl3):δ26.61,116.12,117.77,128.53,132.37,
139.70,196.43.
2 compound of embodiment (1b)
It is being full of N2Glove box in, NiCl is sequentially added into the bottle with sealing plug2·6H2O(11.9mg,
0.05mmol), dppf (33.3mg, 0.06mmol), Zn (13.1mg, 0.2mmol), Zn (CN)2(47.0mg,0.4mmol),
DMAP (91.6mg, 0.75mmol), KI (41.5mg, 0.25mmol), 4- methoxyphenyl methanesulfonates (107.1mg,
0.5mmol), DMF (5mL).It covers lid and moves back out glove box, be placed directly in 80 DEG C of oil baths and heat reaction, be cooled to room after 12h
Temperature, TLC detection reaction.Water quenching is gone out after reaction, Et2O is extracted three times, organic phase washing, and saturated common salt washing merges water
Phase, Et2O is stripped twice, merges organic phase, and anhydrous magnesium sulfate dries, filters concentration rear pillar chromatography.Silica gel column chromatography, elution
Agent: petrol ether/ethyl acetate=10:1, product be white solid 53.6mg, yield 81%,1H NMR purity is greater than 98%.1H
NMR(400MHz,CDCl3): δ 3.86 (s, 3H), 6.95 (d, J=8.8Hz, 2H), 7.58 (d, J=9.2Hz, 2H)13C NMR
(100MHz,CDCl3):δ55.45,103.81,114.67,119.15,133.87,162.76.
3 compound of embodiment (1c)
Using 2 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=40:
1, product is light yellow liquid 20.4mg, and yield 35% and nuclear-magnetism yield are 72%.1H NMR purity is greater than 98%.1H NMR
(400MHz,CDCl3): δ 2.42 (s, 3H), 7.27 (d, J=7.2Hz, 2H), 7.54 (d, J=7.2Hz, 2H)13C NMR
(100MHz,CDCl3):δ21.77,109.28,119.11,129.79,132.00,143.65.
4 compound of embodiment (1d)
Using 2 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate/dichloro
Methane=100:3:1, product are light yellow liquid 33.2mg, and yield 42% and nuclear-magnetism yield are 71%.1H NMR purity is greater than
98%.1H NMR(400MHz,CDCl3): δ 0.93 (t, J=7.2Hz, 3H), 1.29-1.39 (m, 2H), 1.57-1.64 (m,
2H), 2.66 (t, J=7.6Hz, 2H), 7.27 (d, J=8.0Hz, 2H), 7.55 (d, J=8.0Hz, 2H)13C NMR
(100MHz,CDCl3):δ13.78,22.18,33.01,35.74,109.39,111.13,129.14,132.03,148.52。
5 compound of embodiment (1e)
Using 1 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=3:1,
Product is colourless liquid 40.7mg, yield 61%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ2.70
(brs, 1H), 4.76 (s, 2H), 7.47 (d, J=8.0Hz, 2H), 7.62 (d, J=8.0Hz, 2H)
6 compound of embodiment (1f)
Using 2 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate/dichloro
Methane=15:1:1, product are light yellow solid 50.9mg, yield 69%.1H NMR purity is greater than 98%.M.p=70.1-
71.2℃.1H NMR(400MHz,CDCl3,Me4Si): δ 2.41 (s, 3H), 3.91 (s, 3H), 6.78 (s, 1H), 6.81 (d, J=
8.0Hz, 1H), 7.41 (d, J=7.6Hz, 1H)13C NMR(100MHz,CDCl3,Me4Si):δ22.17,55.78,98.60,
111.97,116.75,121.56,133.26,145.69,161.09.IR(neat):3070,3016,2949,2921,2845,
2217,1608,1572,1503,1466,1409,1378,1302,1287,1272,1200,1164,1123,1033,929,
864,742,728.HRMS(ESI)calcd for C9H10NO[M+H]+:148.0757,found 148.0752.
7 compound of embodiment (1g)
Using 1 scheme of embodiment, 6h is reacted at 80 DEG C.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=12:1,
Product is colourless liquid 62.8mg, yield 85%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ6.07(s,
2H), 6.87 (d, J=8.0Hz, 1H), 7.03 (s, 1H), 7.21 (d, J=8.0Hz, 1H)13C NMR(100MHz,CDCl3):δ
102.13,104.77,109.00,111.24,118.74,128.07,147.91,151.42.
8 compound of embodiment (1h)
Using 1 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=12:
1, product is colourless liquid 56.2mg, yield 77%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ2.96
(s, 3H), 6.86-6.88 (m, 2H), 6.93 (d, J=7.2Hz, 1H), 7.26 (dd, J=7.6Hz, 1H)13C NMR
(100MHz,CDCl3):δ40.00,112.60,114.62,116.11,119.23,119.69,129.61,150.11.
9 compound of embodiment (1i)
Using 1 scheme of embodiment, 5h is reacted at 80 DEG C.Column chromatography, eluent: petrol ether/ethyl acetate=10:1, product
For white solid 74.5mg, yield 91%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3,Me4Si):δ3.81
(s,6H),6.65(s,1H),6.75(s,2H).13C NMR(100MHz,CDCl3,Me4Si):δ55.52,105.44,109.74,
113.23,118.62,160.85.
10 compound of embodiment (1j)
Using 1 scheme of embodiment, but ligand is changed to PMePh2, NiCl2·6H2O(5.9mg,0.025mmol),
PMePh2(12.0mg,0.06mmol),Zinc(6.5mg,0.1mmol),Zn(CN)2(47.0mg,0.4mmol),DMAP
(91.6mg, 0.75mmol), 4- benzoylphenyl methanesulfonates (138.2mg, 0.5mmol) and CH3CN (5mL), after adding
In 80 DEG C of reaction 12h.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=10:1, product are white solid 91.5mg, are received
Rate 88%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3): δ 7.52 (t, J=7.6Hz, 2H), 7.64 (t, J=
7.2Hz, 2H), 7.78-7.80 (m, 4H), 7.88 (d, J=8.4Hz, 2H)13C NMR(100MHz,CDCl3):δ115.49,
117.89,128.51,129.93,130.10,132.05,133.20,136.18,141.08,194.90.
11 compound of embodiment (1k)
Using 1 scheme of embodiment, 9h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petroleum ether/methylene chloride=3:2 is arrived
1:1, product are white solid 52.8mg, yield 82%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ
7.81(s,4H).13C NMR(100MHz,CDCl3):δ116.66,116.97,132.76.
12 compound of embodiment (1l)
Using 1 scheme of embodiment, 3h is reacted at 80 DEG C.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=10:1,
Product is white solid 73.9mg, yield 92%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ3.97(s,
3H), 7.76 (d, J=8.4Hz, 2H), 8.15 (d, J=8.4Hz, 2H)13C NMR(100MHz,CDCl3):δ52.58,
116.21,117.82,129.94,132.09,133.75,165.26.
13 compound of embodiment (1m)
Using 1 scheme of embodiment, 7h is reacted at 80 DEG C.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=12:1,
Product is white solid 77.4mg, yield 88%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ1.43(t,
J=6.8Hz, 3H), 4.43 (q, J=6.8Hz, 2H), 7.60 (t, J=8.0Hz, 1H), 7.84 (d, J=7.6Hz, 1H), 8.28
(d, J=8.0Hz, 1H), 8.33 (s, 1H)13C NMR(100MHz,CDCl3):δ14.09,61.64,112.72,117.79,
129.28,131.60,133.06,133.48,135.72,164.43.
14 compound of embodiment (1n)
Using 1 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=3:1,
Product is white solid 35.6mg, yield 68%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ7.46-
7.49 (m, 1H), 8.00 (d, J=8.0Hz, 1H), 8.84 (d, J=4.0Hz, 1H), 8.91 (s, 1H)13C NMR(100MHz,
CDCl3):δ110.02,116.39,123.55,139.17,152.35,152.89.
15 compound of embodiment (1o)
Using 2 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=2:1,
Product is white solid 34.3mg, yield 44%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ7.57
(dd, J=8.0,4.0Hz, 1H), 7.63 (t, J=8.0Hz, 1H), 8.10 (d, J=8.4Hz, 1H), 8.14 (d, J=7.2Hz,
1H), 8.27 (d, J=8.0Hz, 1H), 9.10-9.11 (m, 1H)13C NMR(100MHz,CDCl3):δ112.98,117.19,
122.72,125.80,128.05,132.86,135.47,136.45,147.38,152.43.
16 compound of embodiment (1p)
Using 1 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=7:1
To 5:1, product is white solid 57.9mg, yield 41%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3,
Me4Si):δ0.92(s,3H),1.48-1.65(m,6H),1.98-2.19(m,4H),2.40-2.41(m,2H),2.52(dd,J
=18.8,9.2Hz, 1H), 2.93-2.96 (m, 2H), 7.38-7.43 (m, 2H)13C NMR(100MHz,CDCl3,Me4Si):δ
13.65,21.41,25.28,25.82,28.83,31.31,35.65,37.42,44.40,47.67,50.29,109.41,
119.04,126.09,129.17,132.38,137.79,145.25,220.19.
17 compound of embodiment (1q)
Using 1 scheme of embodiment, 8h is reacted at 50 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=35:1,
Product is white solid 71.6mg, yield 93%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ7.54-
7.64(m,3H),7.82-7.87(m,3H),8.15(s,1H).13C NMR(100MHz,CDCl3):δ109.12,119.11,
126.11,127.49,127.88,128.22,128.89,129.01,132.01,133.94,134.42.
18 compound of embodiment (1r)
Using 1 scheme of embodiment, 6h is reacted at 50 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=35:1,
Product is light yellow liquid 70.9mg, yield 93%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3,Me4Si):
δ 7.48 (dd, J=7.6Hz, 1H), 7.58 (dd, J=7.6Hz, 1H), 7.65 (dd, J=7.6Hz, 1H), 7.87 (d, J=
8.4Hz, 2H), 8.03 (d, J=8.4Hz, 1H), 78.29 (d, J=8.4Hz, 1H)13C NMR(100MHz,CDCl3,
Me4Si):δ109.93,117.70,124.76,124.91,127.39,128.43,128.52,132.13,132.46,
132.72,133.14.
19 compound of embodiment (1s)
Using 1 scheme of embodiment, 9h is reacted at 80 DEG C.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=30:1,
Product is white solid 66.3mg, yield 74%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ7.42-
7.50 (m, 3H), 7.57-7.59 (m, 2H), 7.66 (d, J=8.8Hz, 2H), 7.71 (d, J=8.4Hz, 2H)13C NMR
(100MHz,CDCl3):δ110.78,118.87,127.13,127.63,128.58,129.03,132.50,139.04,
145.54.
20 compound of embodiment (1t)
Using 1 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate/dichloro
Methane=100:3:1, product are white solid 71.3mg, yield 74%.1H NMR purity is greater than 98%.1H NMR(400MHz,
CDCl3): δ 2.40 (s, 3H), 7.27 (d, J=8.8Hz, 2H), 7.47 (d, J=7.2Hz, 2H), 7.62-7.68 (m, 4H)13C
NMR(100MHz,CDCl3):δ21.06,110.38,118.93,126.92,127.30,129.73,132.42,136.09,
138.63,145.43.
21 compound of embodiment (1u)
Using 1 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=30:
1, product is white solid 86.7mg, yield 83%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ3.85
(s, 3H), 6.95 (d, J=8.0Hz, 1H), 7.09 (s, 1H), 7.15 (d, J=7.2Hz, 2H), 7.38 (t, J=7.6Hz,
1H),7.63-7.69(m,4H).13C NMR(100MHz,CDCl3):δ55.22,110.84,112.94,113.73,118.78,
119.49,127.60,130.02,132.39,140.43,145.32,159.99.
22 compound of embodiment (1v)
Using 1 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=30:
1, product is white solid 78.9mg, yield 80%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ7.14-
7.18 (m, 2H), 7.54-7.57 (m, 2H), 7.63 (d, J=8.0Hz, 2H), 7.70 (d, J=7.6Hz, 2H)13C NMR
(100MHz,CDCl3):δ110.81,115.98(2JC-F=21.5Hz), 118.71,127.43,128.84 (3JC-F=8.2Hz),
132.51,135.15(4JC-F=3.7Hz), 144.44,163.05 (1JC-F=246.9Hz)19F NMR(376.1MHz,CDCl3)
δ-113.13.
23 compound of embodiment (1w)
Using 1 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel column chromatography, eluent: petroleum ether/methylene chloride/acetic acid
Ethyl ester=10:1.5:1, product are white solid 90.6mg, yield 89%.1H NMR purity is greater than 98%.1H NMR(400MHz,
CDCl3): δ 7.71 (d, J=7.6Hz, 4H), 7.79 (d, J=7.6Hz, 4H)13C NMR(100MHz,CDCl3):δ112.33,
118.36,127.89,132.82,143.49.
24 compound of embodiment (1x)
Using 1 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=30:
1, product is white solid 78.4mg, yield 85%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ7.40
(d, J=13.2Hz, 2H), 7.55 (s, 1H), 7.65 (m, 4H)13C NMR(100MHz,CDCl3):δ110.29,118.83,
122.51,125.78,126.67,127.03,132.54,139.82,140.16.
25 compound of embodiment (2a)
Using 1 scheme of embodiment, 12h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=20:
1, product is white solid 50.3mg, yield 65%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ2.49
(t, J=13.2,4.8Hz, 2H), 2.84 (t, J=8.4Hz, 2H), 6.87 (t, J=4.8Hz, 1H), 7.13-7.15 (m, 1H),
7.23-7.29(m,2H),7.43-7.45(m,1H).13C NMR(100MHz,CDCl3):δ23.63,25.96,114.29,
117.04,124.64,127.12,127.87,128.59,129.04,134.09,143.81.
26 compound of embodiment (2b)
Using 1 scheme of embodiment, 8h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=20:1,
Product is white solid 70.5mg, yield 91%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ2.52(t,
J=8.4Hz, 2H), 2.88 (t, J=8.4Hz, 2H), 7.12-7.16 (m, 3H), 7.20-7.29 (m, 2H)13C NMR
(100MHz,CDCl3):δ24.52,26.52,109.47,119.54,126.99,127.86,130.14,131.01,135.26,
141.54.
27 compound of embodiment (2c)
Using 1 scheme of embodiment, 7h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=15:1,
Product is white solid 78.9mg, yield 86%.1H NMR purity is greater than 98%.M.p.:59.3-61.2℃.1H NMR
(400MHz,CDCl3):δ6.14(s,1H),6.39(s,1H),7.43-7.44(m,2H),7.50-7.58(m,2H),7.85-
7.87 (m, 2H), 8.10 (t, J=8.4Hz, 2H)13C NMR(100MHz,CDCl3):δ118.33,122.01,124.09,
125.13,126.42,126.90,127.04,128.60,130.02,130.09,131.62,133.49,134.69.IR
(neat):3028,2211,1635,1601,1492,1452,1434,1417,1077,1027,976,945,926,834,761,
699.HRMS(EI)for C13H13N[M]+:calcd 183.1048,found 183.1042.
28 compound of embodiment (2d)
Using 1 scheme of embodiment, 7h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=30:1,
Product is white solid 68.0mg, yield 76%.1H NMR purity is greater than 98%.1H NMR(400MHz,CDCl3):δ1.76-
1.83(m,1H),1.98-2.03(m,1H),2.23-2.33(m,1H),2.35-2.39(m,2H),2.46-2.52(m,1H),
2.79-2.80 (m, 1H), 6.69-6.70 (m, 1H), 7.17-7.25 (m, 3H), 7.32 (t, J=7.6Hz, 2H)13C NMR
(100MHz,CDCl3):δ27.08,28.47,33.41,38.18,112.15,119.40,126.53,126.57,128.54,
144.50,144.82.IR(neat):3057,2226,1590,1508,1402,1340,1252,1200,944,859,802,
774,658,660.HRMS(ESI)calcd for C13H10N[M+H]+:180.0808,found 180.0808.
29 compound of embodiment (2e)
Using 1 scheme of embodiment, 7h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=20:1,
Product is white solid 99.2mg, yield 90% (Z:E=3.2:1).1H NMR purity is greater than 98%.1H NMR(400MHz,
CDCl3):δ3.66(s,2H),3.78(s,0.63H),6.94(s,1H),7.24-7.38(m,11H),7.69-7.71(m,2H)
.13C NMR(100MHz,CDCl3):δ35.33,42.01,110.56,113.83,118.58,120.16,127.10,127.21,
128.20,128.54,128.67,128.70,128.75,128.77,128.80,128.84,129.44,129.99,133.39,
133.54,136.24,136.32,143.92,145.11.
30 compound of embodiment (1a)
Using 1 scheme of embodiment, substrate is changed to 4-acetylphenyl 4-methylbenzenesulfonate
(145.2mg,0.5mmol).12h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=5:1, product are
White solid 69.0mg, yield 95%.1H NMR purity is greater than 98%.
31 compound of embodiment (1a)
Using 1 scheme of embodiment, substrate is changed to 4-acetylphenyl trifluoromethanesulfonate
(134.1mg,0.5mmol).12h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=5:1, product are
White solid 67.2mg, yield 93%.1H NMR purity is greater than 98%.
32 compound of embodiment (1a)
Using 2 scheme of embodiment, substrate be changed to 4-acetylphenyl dimethylsulfamate (121.6mg,
0.5mmol).9h is reacted at 100 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=6:1, product are white solid
45.5mg, yield 63%.1H NMR purity is greater than 98%.
32 compound of embodiment (1b)
Using 2 scheme of embodiment, substrate be changed to 4-methoxyphenyl sulfurofluoridate (103.1mg,
0.5mmol)(121.6mg,0.5mmol).12h is reacted at 80 DEG C.Silica gel plate layer chromatography, eluent: petrol ether/ethyl acetate=
12:1, product are white solid 51.1mg, yield 77%.1H NMR purity is greater than 98%.
33 compound of embodiment (1k)
It is being full of N2Glove box in, NiCl is sequentially added into the bottle with sealing plug2·6H2O(11.9mg,
0.05mmol),dppf(33.3mg,0.06mmol),Zinc(13.1mg,0.2mmol),Zn(CN)2(93.9mg,0.8mmol),
DMAP (183.3mg, 1.50mmol), 4-chlorophenyl sulfurofluoridate (105.3mg, 0.5mmol) and
CH3CN(5mL).It covers lid and moves back out glove box, be placed directly in 80 DEG C of oil baths and heat reaction, be cooled to room temperature, TLC after 12h
Silica gel filters after detection, and ethyl acetate is washed, concentration rear pillar chromatography.Silica gel plate layer chromatography, eluent: petroleum ether/methylene chloride=3:2
To 1:1, product is white solid 58.7mg, yield 92%.1H NMR purity is greater than 98%.
34 compound of embodiment (1a)
It is being full of N2Glove box in, NiCl is sequentially added into the bottle with sealing plug2·6H2O(5.9mg,
0.025mmol), dppf (16.6mg, 0.03mmol), Zn (6.5mg, 0.1mmol), Zn (CN)2(47.0mg,0.4mmol),
DMAP (61.1mg, 0.5mmol), 4- acetylphenyl methanesulfonates (107.1mg, 0.5mmol), CH3CN(5mL).It covers
Son moves back out glove box, is placed directly in 80 DEG C of oil baths and heats reaction, room temperature is cooled to after 12h, silica gel filters after TLC detection, second
Acetoacetic ester is washed, concentration rear pillar chromatography.Eluent: petrol ether/ethyl acetate=5:1, product are white solid 64.0mg, yield
88%,1H NMR purity is greater than 98%.
35 compound of embodiment (1a)
Using 34 scheme of embodiment, ligand is changed to dppb (12.8mg, 0.03mmol).12h is reacted at 80 DEG C.Silicagel column
Chromatography, eluent: petrol ether/ethyl acetate=5:1, product be white solid 64.8mg, yield 89%,1H NMR purity is greater than
98%.
36 compound of embodiment (1a)
Using 34 scheme of embodiment, ligand is changed to Xantphos (17.4mg, 0.03mmol).12h is reacted at 80 DEG C.Silicon
Plastic column chromatography, eluent: petrol ether/ethyl acetate=5:1.Product is white solid 16.4mg, yield 23%.1H NMR purity
Greater than 98%.
37 compound of embodiment (1a)
Using 34 scheme of embodiment, ligand is changed to DPEphos (16.2mg, 0.03mmol).12h is reacted at 80 DEG C.Silicon
Plastic column chromatography, eluent: petrol ether/ethyl acetate=5:1.Product is white solid 43.3mg, yield 60%.1H NMR purity
Greater than 98%
38 compound of embodiment (1a)
Using 34 scheme of embodiment, ligand is changed to PMe2Ph(8.3mg,0.06mmol).12h is reacted at 80 DEG C.Silica gel
Column chromatography, eluent: petrol ether/ethyl acetate=5:1.Product is white solid 52.9mg, yield 73%.1H NMR purity is big
In 98%.
39 compound of embodiment (1a)
Using 34 scheme of embodiment, ligand is changed to PMePh2(12.0mg,0.06mmol).12h is reacted at 80 DEG C.Silica gel
Column chromatography, eluent: petrol ether/ethyl acetate=5:1.Product is white solid 52.9mg, yield 73%.1H NMR purity is big
In 98%.
40 compound of embodiment (1a)
Using 34 scheme of embodiment, ligand is changed to PPh3(12.0mg,0.06mmol).12h is reacted at 80 DEG C.Silicagel column
Chromatography, eluent: petrol ether/ethyl acetate=5:1.Product is white solid 13.2mg, yield 18%.1H NMR purity is greater than
98%.
41 compound of embodiment (1a)
Using 34 scheme of embodiment, catalyst is changed to NiBr2·DME(7.7mg,0.06mmol).It is reacted at 80 DEG C
12h.Silica gel column chromatography, eluent: petrol ether/ethyl acetate=5:1.Product is white solid 63.1mg, yield 87%.1H
NMR purity is greater than 98%.
42 compound of embodiment (1a)
Using 34 scheme of embodiment, catalyst is changed to NiI2(7.8mg,0.06mmol).12h is reacted at 80 DEG C.Silica gel
Column chromatography, eluent: petrol ether/ethyl acetate=5:1.Product is white solid 59.7mg, yield 82%.1H NMR purity is big
In 98%
43 compound of embodiment (1a)
Using 34 scheme of embodiment, solvent is changed to DMA (5mL).12h is reacted at 80 DEG C.Silica gel column chromatography, eluent:
Petrol ether/ethyl acetate=5:1.Product is white solid 62.5mg, yield 87%.1H NMR purity is greater than 98%
44 compound of embodiment (1a)
Using 34 scheme of embodiment, solvent is changed to NMP (5mL).12h is reacted at 80 DEG C.Silica gel column chromatography, eluent:
Petrol ether/ethyl acetate=5:1.Product is white solid 42.4mg, yield 58%.1H NMR purity is greater than 98%.
45 compound of embodiment (1a)
Using 34 scheme of embodiment, temperature is changed to 60 DEG C.12h is reacted at 60 DEG C.Silica gel column chromatography, eluent: petroleum
Ether/ethyl acetate=5:1.Product is white solid 61.9mg, yield 85%.1H NMR purity is greater than 98%.
46 compound of embodiment (1b)
It is being full of N2Glove box in, NiCl is sequentially added into the bottle with sealing plug2·6H2O(11.9mg,
0.05mmol), dppf (33.3mg, 0.06mmol), Zn (13.1mg, 0.2mmol), Zn (CN)2(47.0mg,0.4mmol),
DMAP (91.6mg, 0.75mmol), NaI (37.5mg, 0.25mmol), 4- methoxyphenyl methanesulfonates (107.1mg,
0.5mmol), DMF (5mL).It covers lid and moves back out glove box, be placed directly in 80 DEG C of oil baths and heat reaction, be cooled to room after 12h
Temperature, TLC detection reaction.Water quenching is gone out after reaction, Et2O is extracted three times, organic phase washing, and saturated common salt washing merges water
Phase, Et2O is stripped twice, merges organic phase, and anhydrous magnesium sulfate dries, filters concentration rear pillar chromatography.Silica gel column chromatography, elution
Agent: petrol ether/ethyl acetate=10:1, product be white solid 43.2mg, yield 65%,1H NMR purity is greater than 98%.
47 compound of embodiment (1b)
Using 46 scheme of embodiment, additive is changed to Et4NI(64.3mg,0.25mmol).Silica gel column chromatography, elution
Agent: petrol ether/ethyl acetate=10:1, product are white solid 45.9mg, yield 70%.1H NMR purity is greater than 98%.
Claims (13)
1. a kind of preparation method of aromatic nitrile compounds shown in formula I comprising following steps: in inert gas shielding
Under, in a solvent, under the conditions of existing for nickel complex, metallic zinc and the additive, the aryl as shown in Formula II or heteroaryl
Sulfonates compounds and cyanylation agent carry out cross-coupling reaction as follows；Wherein, the additive is
4-dimethylaminopyridine, the cyanylation agent are zinc cyanide；
In aromatic nitrile compounds shown in formula I and aryl or heteroaryl sulfonates compounds as shown in Formula II,
N is selected from any integer between 0- [M-1], and wherein M indicates the maximum substitution number on ring α；
R1It is identical or different, it is each independently selected from halogen, C1-C6Straight or branched alkoxyl ,-CN ,-C (=O) ORa、-
NRbRc,-C (=O) Rd,-C (=O) NReRf、RgSubstituted C3-C10Aryl or heteroaryl or RhSubstituted C1-C6Straight chain or
Branched alkyl；Wherein, Ra、Rb、Rc、Rd、Re、Rf、RgAnd RhIt is each independently selected from-H, halogen ,-OH ,-CN, C1-C4Straight chain
Or branched alkoxy and C1-C4One of linear or branched alkyl group or a variety of；
Alternatively, the adjacent substituted R of any two1The atom on ring α being respectively connected with it collectively forms one with ring α and ring
Carbocyclic ring or carbon heterocyclic, the carbocyclic ring or carbon heterocyclic are 3-10 member ring, and the carbon heterocyclic contains 1-4 and is selected from the miscellaneous of O, N and S
Atom；
- OS (=O)2R in R is selected from halogen, C1-C6Linear or branched alkyl group, C1-C6Linear chain or branched chain halogenated alkyl or
RiSubstituted phenyl；Wherein, RiSelected from halogen, C1-C6Linear or branched alkyl group or-NRjRk, wherein RjAnd RkEach independently
Selected from C1-C4Linear or branched alkyl group；
The ring α is aromatic ring or heteroaromatic；Wherein, when the ring α is aromatic ring, the aromatic ring refers to any stable
May be up in each ring 6 atoms monocycle or polycyclic carbocyclic ring, it is described it is polycyclic at least one ring be aromatic rings；When described
Aromatic ring is polycyclic and when wherein there is non-aromatic ring ,-OS (=O)2R and-CN connection be respectively by " aromatic rings " into
Capable；Wherein, when the ring α is heteroaromatic, the heteroaromatic, which refers to, may be up to 6 atoms in any stable each ring
Stabilization monocycle or polycyclic, it is described it is polycyclic at least one ring be aromatic rings and miscellaneous selected from O, N and S containing 1-4
Atom；When the heteroaromatic be it is polycyclic and wherein exist non-aromatic ring or do not include hetero atom when ,-OS (=O)2R and-CN
Connection is carried out by " containing heteroatomic aromatic rings " respectively.
2. preparation method as described in claim 1, which is characterized in that wherein,
N is 0,1 or 2；
And/or work as Ra、Rb、Rc、Rd、Re、Rf、RgAnd RhIn it is any be halogen when, the halogen be fluorine, chlorine, bromine or iodine；
And/or work as Ra、Rb、Rc、Rd、Re、Rf、RgAnd RhIn it is any be C1-C4Straight or branched alkoxyl when, the C1-C4
Straight or branched alkoxyl be C1-C3Straight or branched alkoxyl, preferably methoxyl group, ethyoxyl, propoxyl group or isopropyl oxygen
Base；
And/or work as Ra、Rb、Rc、Rd、Re、Rf、RgAnd RhIn it is any be C1-C4Linear or branched alkyl group when, the C1-C4's
Linear or branched alkyl group is C1-C3Linear or branched alkyl group, preferably methyl, ethyl, propyl or isopropyl；
And/or work as R1When for halogen, the halogen is fluorine, chlorine, bromine or iodine；
And/or work as R1For C1-C6Straight or branched alkoxyl when, the C1-C6Straight or branched alkoxyl be C1-C3's
Straight or branched alkoxyl, preferably methoxyl group, ethyoxyl, propoxyl group or isopropoxy；
And/or work as R1For-C (=O) ORaWhen, RaFor C1-C4Linear or branched alkyl group, preferably methyl, ethyl, propyl or different
Propyl；
And/or work as R1For-NRbRcWhen, RbAnd RcIt is each independently C1-C4Linear or branched alkyl group, preferably methyl, second
Base, propyl or isopropyl；
And/or work as R1For-C (=O) RdWhen, RdFor C1-C4Linear or branched alkyl group, preferably methyl, ethyl, propyl or different
Propyl；
And/or work as R1For-C (=O) NReRfWhen, ReAnd RfIt is each independently C1-C4Linear or branched alkyl group, preferably first
Base, ethyl, propyl or isopropyl；
And/or work as R1For RgSubstituted C3-C10Aryl or heteroaryl when, the C3-C10Aryl or heteroaryl be phenyl
Or thienyl；
And/or work as R1For RhSubstituted C1-C6Linear or branched alkyl group when, the C1-C6Linear or branched alkyl group be C1-
C3Linear or branched alkyl group, preferably methyl, ethyl, propyl or isopropyl；
And/or as the adjacent substituted R of any two1The atom on ring α being respectively connected with it collectively forms one and ring α and ring
Carbocyclic ring or carbon heterocyclic when, the carbocyclic ring or carbon heterocyclic are 3-5 member ring, and the carbon heterocyclic contains 1 or 2 selected from O, N and S
Hetero atom；
And/or when n is 1, R1It is preferably selected from methyl, normal-butyl, methoxyl group, amino, acetyl group, methoxycarbonyl, ethyoxyl
Carbonyl, cyano or phenyl；When n is 2, R1It is identical or different, it is preferably selected from methyl or methoxy each independently；Or two
R1The atom on ring α being respectively connected with it collectively forms dioxolyl；
And/or work as RiWhen for halogen, the halogen is fluorine, chlorine, bromine or iodine；
And/or work as RiFor C1-C6Linear or branched alkyl group when, the C1-C6Linear or branched alkyl group be C1-C3Straight chain
Or branched alkyl, preferably methyl, ethyl, propyl or isopropyl；
And/or work as RiFor-NRjRkWhen ,-the NRjRkMiddle RjAnd RkIt is each independently methyl, ethyl, propyl or isopropyl；
And/or when R is halogen, the halogen is fluorine, chlorine, bromine or iodine；
And/or when R is C1-C6Linear or branched alkyl group when, the C1-C6Linear or branched alkyl group be C1-C3Straight chain
Or branched alkyl, preferably methyl, ethyl, propyl or isopropyl；
And/or when R is C1-C6Linear chain or branched chain halogenated alkyl when, the C1-C6Linear chain or branched chain halogenated alkyl be C1-
C3Linear chain or branched chain halogenated alkyl, preferably trifluoromethyl.
3. preparation method as described in claim 1, which is characterized in that wherein,
- the OS (=O)2R is fluorosulfonyl, trifyl, mesyl, p-methylphenyl sulfonyl or aminosulfonyl
Base；
And/or the aromatic ring is monocycle class aromatic rings or two ring class polycyclic aromatic rings, preferably phenyl ring or naphthalene nucleus；
And/or the heteroaromatic is monocycle class pyridine ring or bicyclic class quinoline ring.
4. preparation method as described in claim 1, which is characterized in that the aryl as shown in Formula II or heteroaryl sulfonic acid
Ester type compound and aromatic nitrile compounds shown in formula I are following any pair of compound:
5. preparation method as described in claim 1, which is characterized in that the aromatic nitrile compounds shown in formula I
In preparation method,
The inert protective gas is one of nitrogen, helium, argon gas and neon or a variety of；
And/or the molar ratio of the aryl as shown in Formula II or heteroaryl sulfonates compounds and DMAP are 1:0.1-
1:10, preferably 1:1-1:1.5；
And/or the molar ratio of the aryl as shown in Formula II or heteroaryl sulfonates compounds and the metallic zinc
For 1:0.01-1:10, more preferably 1:0.1-1:1, further preferably 1:0.2-1:0.4；
And/or the nickel complex is NiBr2(PPh3)2And/or NiCl2(dppf)；
And/or mole of the aryl as shown in Formula II or heteroaryl sulfonates compounds and the nickel complex
Than for 1:0.01-1:1, more preferable 1:0.02-1:0.50, further preferred 1:0.05-1:0.10；
And/or the aryl as shown in Formula II or heteroaryl sulfonates compounds and the cyanylation agent rub
You are than being 1:0.1-1:10, more preferable 1:0.5-1:2, further preferred 1:0.6-1:1.2 or preferred 1:0.8；
And/or the solvent be aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent, nitrile solvents, amide solvent and
One of sulfoxide type solvents are a variety of；One of the preferred benzene of the aromatic hydrocarbon solvent, toluene and dimethylbenzene are a variety of；Institute
The preferred ether of the ether solvent stated, Isosorbide-5-Nitrae-one of dioxane and tetrahydrofuran or a variety of；The halogenated hydrocarbon solvent
It is preferred that chlorinated hydrocarbon solvent；One of the preferred methylene chloride of the chlorinated hydrocarbon solvent, dichloroethanes and chloroform are a variety of；
The preferred acetonitrile of the nitrile solvents；The preferred N,N-dimethylformamide of the amide solvent, DMAC N,N' dimethyl acetamide
(DMA) and one of hexamethyl phosphoramide or a variety of；The preferred dimethyl sulfoxide of the sulfoxide type solvents；The solvent is more
It is preferred that one of acetonitrile, N,N-dimethylformamide and DMAC N,N' dimethyl acetamide or a variety of；
And/or the molal volume of the aryl as shown in Formula II or heteroaryl sulfonates compounds and the solvent
Than for 0.01mmol/mL-1mmol/mL, preferably 0.1mmol/mL-0.5mmol/mL；
And/or the reaction temperature of the cross-coupling reaction be -100 DEG C -500 DEG C, preferably 0 DEG C -150 DEG C, more preferable 50
DEG C -100 DEG C, further preferred 60 DEG C -80 DEG C；
And/or the reaction time of the cross-coupling reaction is 0.1-200h, preferably 3-12h.
6. preparation method as described in claim 1, which is characterized in that the aromatic nitrile compounds shown in formula I
In preparation method,
There are also other additives in addition to the additive DMAP in the reaction system, other described additives are quaternary ammonium salt
And/or inorganic salts；Wherein, the preferred tetraethyl ammonium iodide of the quaternary ammonium salt；The preferred sodium iodide of the inorganic salts, potassium iodide and
It is one or more in lithium iodide, more preferable potassium iodide；When including also quaternary ammonium salt and/or inorganic salts in the reaction system, institute
The molar ratio of the aryl as shown in Formula II or heteroaryl sulfonates compounds and the quaternary ammonium salt and/or inorganic salts stated is excellent
It is selected as 1:0.1-1:10, more preferably 1:0.5-1:1；
And/or after the nickel complex carries out complexed in situ in the reaction system by nickel cocatalyst and its applicable ligand
It participates in reacting again；Wherein, the nickel cocatalyst is selected from Ni (cod)2、NiCl2、NiBr2、NiI2、NiBr2(diglyme)、
NiCl2(glyme)、NiBr2(DME)、NiF2And NiCl2·6H2One of O or a variety of, preferably NiBr2(DME)、NiI2With
NiCl2·6H2One of O or a variety of；The applicable ligand of the nickel cocatalyst is selected from triphenylphosphine, triethyl phosphine, three
Bis- (diphenyl phosphine) second of butyl phosphine, tricyclohexyl phosphine, double diphenylphosphine methane, dimethylphenylphosphine, diphenyl methyl phosphine, 1,2-
Bis- (diphenylphosphine) propane of alkane, 1,3-, bis- (diphenylphosphine) butane of 1,4-, bis- (diphenylphosphine) ferrocene of 1,1'-, 9,9- diformazan
The double diphenylphosphine xanthenes of base -4,5-, (the di-t-butyl phosphine) -9,9- xanthphos of 4,5- bis- and 3- (dicyclohexylphosphontetrafluoroborate
Base) one of -1- methyl -2- phenyl -1H- indoles or a variety of, more preferably double diphenylphosphine methane, diphenyl methyl phosphine, 1,
Bis- (diphenyl phosphine) ethane of 2-, bis- (diphenylphosphine) propane of 1,3-, bis- (diphenylphosphine) butane of 1,4-, 1,1'- bis- (diphenylphosphines)
Ferrocene and 9, one of bis- diphenylphosphine xanthenes of 9- dimethyl -4,5- or a variety of, further preferred diphenyl methyl phosphine,
One of bis- (diphenylphosphine) ferrocene of 1,1'- and the double diphenylphosphine xanthenes of 9,9- dimethyl -4,5- are a variety of；Described
Nickel cocatalyst and the molar ratio for being applicable in ligand are preferably 1:1~1:10, more preferable 1:1~1:5, further preferably
1:1.2。
7. a kind of preparation method of the alkenyl nitrile compounds as shown in formula III comprising following steps: in inert gas shielding
Under, in a solvent, under the conditions of existing for nickel complex, metallic zinc and the additive, the olefin sulfonic acid esters as shown in IV
It closes object and cyanylation agent carries out cross-coupling reaction as follows；Wherein, the additive is 4- dimethylamino
Pyridine；The cyanylation agent is zinc cyanide；
In alkenyl nitrile compounds and the olefin sulfonic acid ester type compound as shown in formula IV as shown in formula III,
R2、R3And R4It is each independently selected from-H ,-(CH2)x-RmSubstituted C3-C10Aryl or heteroaryl or RnSubstituted C1-
C6Linear or branched alkyl group；Wherein, RmAnd RnIt is each independently selected from-H, halogen ,-OH ,-CN, C1-C4Linear chain or branched chain alkane
Oxygroup and C1-C4One of linear or branched alkyl group or a variety of；X is selected from any integer between 0-4；
Alternatively, R2With R3Or R2With R4One is collectively formed by RnThe monocycle of substituted 5-10 member or polycyclic carbocyclic ring or carbon heterocyclic, institute
The carbon heterocyclic stated contains the 1-4 hetero atoms for being selected from O, N and S；The monocycle of the 5-10 member or polycyclic carbocyclic ring or carbon heterocyclic are
Saturation or semi-saturation ring；
- OS (=O)2R in R is selected from halogen, C1-C6Linear or branched alkyl group, C1-C6Linear chain or branched chain halogenated alkyl or
RiSubstituted phenyl；Wherein, RiSelected from halogen, C1-C6Linear or branched alkyl group or-NRjRk, wherein RjAnd RkEach independently
Selected from C1-C4Linear or branched alkyl group.
8. preparation method as claimed in claim 7, which is characterized in that wherein,
X is 0,1,2 or 3；
And/or work as RmAnd RnIn it is any be halogen when, the halogen is preferably fluorine, chlorine, bromine or iodine；
And/or work as RmAnd RnIn it is any be C1-C4Straight or branched alkoxyl when, the C1-C4Linear chain or branched chain alcoxyl
Base is C1-C3Straight or branched alkoxyl, preferably methoxyl group, ethyoxyl, propoxyl group or isopropoxy；
And/or work as RmAnd RnIn it is any be C1-C4Linear or branched alkyl group when, the C1-C4Linear or branched alkyl group be
C1-C3Linear or branched alkyl group, preferably methyl, ethyl, propyl or isopropyl；
And/or work as RiWhen for halogen, the halogen is fluorine, chlorine, bromine or iodine；
And/or work as RiFor C1-C6Linear or branched alkyl group when, the C1-C6Linear or branched alkyl group be C1-C3Straight chain
Or branched alkyl, preferably methyl, ethyl, propyl or isopropyl；
And/or work as RiFor-NRjRkWhen ,-the NRjRkMiddle RjAnd RkIt is each independently methyl, ethyl, propyl or isopropyl；
And/or when R is halogen, the halogen is fluorine, chlorine, bromine or iodine；
And/or when R is C1-C6Linear or branched alkyl group when, the C1-C6Linear or branched alkyl group be C1-C3Straight chain
Or branched alkyl, preferably methyl, ethyl, propyl or isopropyl；
And/or when R is C1-C6Linear chain or branched chain halogenated alkyl when, the C1-C6Linear chain or branched chain halogenated alkyl be C1-
C3Linear chain or branched chain halogenated alkyl, preferably trifluoromethyl.
9. preparation method as claimed in claim 7, which is characterized in that wherein,
- the OS (=O)2R is fluorosulfonyl, trifyl, mesyl, p-methylphenyl sulfonyl or aminosulfonyl
Base；
And/or described-(CH2)x-RmSubstituted C3-C10Aryl or heteroaryl in, the C3-C10Aryl or heteroaryl
Base is C6-C10Aryl, preferably phenyl or naphthyl；
And/or the RnSubstituted C1-C6Linear or branched alkyl group in, the C1-C6Linear or branched alkyl group be
C1-C3Linear or branched alkyl group, preferably methyl, ethyl, propyl or isopropyl；
And/or the monocycle or the preferred monocycle of polycyclic carbocyclic ring or bicyclic carbocyclic of the 5-10 member, preferably cyclohexene or benzo ring
Hexene.
10. preparation method as claimed in claim 7, which is characterized in that the olefin sulfonic acid esters as shown in formula IV
Closing object and the alkenyl nitrile compounds as shown in formula III is following any pair of compound:
11. preparation method as claimed in claim 7, which is characterized in that the alkenyl nitrile compounds as shown in formula III
Preparation method in,
The inert protective gas is one of nitrogen, helium, argon gas and neon or a variety of；
And/or the molar ratio of olefin sulfonic acid ester type compound and DMAP as shown in formula IV is 1:0.1-1:10, preferably
For 1:1-1:1.5；
And/or the molar ratio of the olefin sulfonic acid ester type compound as shown in formula IV and the metallic zinc is 1:0.01-
1:10, preferably 1:0.1-1:1, further preferably 1:0.2-1:0.4；
And/or the nickel complex is NiBr2(PPh3)2And/or NiCl2(dppf)；
And/or the molar ratio of the olefin sulfonic acid ester type compound as shown in formula IV and the nickel complex is 1:
0.01-1:1, preferably 1:0.02-1:0.50, further preferred 1:0.05-1:0.10；
And/or the molar ratio of the olefin sulfonic acid ester type compound as shown in formula IV and the cyanylation agent is 1:
0.1-1:10, more preferable 1:0.5-1:2, further preferred 1:0.6-1:1.2 or preferred 1:0.8；
And/or the solvent be aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent, nitrile solvents, amide solvent and
One of sulfoxide type solvents are a variety of；One of the preferred benzene of the aromatic hydrocarbon solvent, toluene and dimethylbenzene are a variety of；Institute
The preferred ether of the ether solvent stated, Isosorbide-5-Nitrae-one of dioxane and tetrahydrofuran or a variety of；The halogenated hydrocarbon solvent
It is preferred that chlorinated hydrocarbon solvent；One of the preferred methylene chloride of the chlorinated hydrocarbon solvent, dichloroethanes and chloroform are a variety of；
The preferred acetonitrile of the nitrile solvents；The preferred N,N-dimethylformamide of the amide solvent, DMAC N,N' dimethyl acetamide
(DMA) and one of hexamethyl phosphoramide or a variety of；The preferred dimethyl sulfoxide of the sulfoxide type solvents；The solvent is more
It is preferred that one of acetonitrile, N,N-dimethylformamide and DMAC N,N' dimethyl acetamide or a variety of；
And/or the molal volume ratio of the olefin sulfonic acid ester type compound as shown in formula IV and the solvent is
0.01mmol/mL-1mmol/mL, preferably 0.1mmol/mL-0.5mmol/mL；
And/or the reaction temperature of the cross-coupling reaction be -100 DEG C -500 DEG C, preferably 0 DEG C -150 DEG C, more preferable 50
DEG C -100 DEG C, further preferred 60 DEG C -80 DEG C；
And/or the reaction time of the cross-coupling reaction is 0.1-200h, preferably 3-12h.
12. preparation method as claimed in claim 7, which is characterized in that the alkenyl nitrile compounds as shown in formula III
Preparation method in,
There are also other additives in addition to the additive DMAP in the reaction system, other described additives are quaternary ammonium salt
And/or inorganic salts；Wherein, the preferred tetraethyl ammonium iodide of the quaternary ammonium salt；The preferred sodium iodide of the inorganic salts, potassium iodide and
It is one or more in lithium iodide, more preferable potassium iodide；When including also quaternary ammonium salt and/or inorganic salts in the reaction system, institute
The molar ratio of the olefin sulfonic acid ester type compound as shown in formula IV and the quaternary ammonium salt and/or inorganic salts stated is 1:0.1-1:
10, preferably 1:0.5-1:1；
And/or after the nickel complex carries out complexed in situ in the reaction system by nickel cocatalyst and its applicable ligand
It participates in reacting again；Wherein, the nickel cocatalyst is selected from Ni (cod)2、NiCl2、NiBr2、NiI2、NiBr2(diglyme)、
NiCl2(glyme)、NiBr2(DME)、NiF2And NiCl2·6H2One of O or a variety of, preferably NiBr2(DME)、NiI2With
NiCl2·6H2One of O or a variety of；The applicable ligand of the nickel cocatalyst is selected from triphenylphosphine, triethyl phosphine, three
Bis- (diphenyl phosphine) second of butyl phosphine, tricyclohexyl phosphine, double diphenylphosphine methane, dimethylphenylphosphine, diphenyl methyl phosphine, 1,2-
Bis- (diphenylphosphine) propane of alkane, 1,3-, bis- (diphenylphosphine) butane of 1,4-, bis- (diphenylphosphine) ferrocene of 1,1'-, 9,9- diformazan
The double diphenylphosphine xanthenes of base -4,5-, (the di-t-butyl phosphine) -9,9- xanthphos of 4,5- bis- and 3- (dicyclohexylphosphontetrafluoroborate
Base) one of -1- methyl -2- phenyl -1H- indoles or a variety of, more preferably double diphenylphosphine methane, diphenyl methyl phosphine, 1,
Bis- (diphenyl phosphine) ethane of 2-, bis- (diphenylphosphine) propane of 1,3-, bis- (diphenylphosphine) butane of 1,4-, 1,1'- bis- (diphenylphosphines)
Ferrocene and 9, one of bis- diphenylphosphine xanthenes of 9- dimethyl -4,5- or a variety of, further preferred diphenyl methyl phosphine,
One of bis- (diphenylphosphine) ferrocene of 1,1'- and the double diphenylphosphine xanthenes of 9,9- dimethyl -4,5- are a variety of；Described
The molar ratio of nickel cocatalyst and the ligand is preferably 1:1~1:10, more preferable 1:1~1:5, and further preferred 1:
1.2。
13. a kind of aromatic nitriles as shown in following structures or alkenyl nitrile compounds:
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| CN115490613A (en) * | 2022-09-05 | 2022-12-20 | 浙江工业大学 | Preparation method of aromatic nitrile compound |
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| CN115490613B (en) * | 2022-09-05 | 2023-07-25 | 浙江工业大学 | Preparation method of aromatic nitrile compound |
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