CN110117237B - Preparation method of aromatic nitrile or alkenyl nitrile compound - Google Patents
Preparation method of aromatic nitrile or alkenyl nitrile compound Download PDFInfo
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- CN110117237B CN110117237B CN201810113897.7A CN201810113897A CN110117237B CN 110117237 B CN110117237 B CN 110117237B CN 201810113897 A CN201810113897 A CN 201810113897A CN 110117237 B CN110117237 B CN 110117237B
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- -1 aromatic nitrile Chemical class 0.000 title claims abstract description 190
- 238000002360 preparation method Methods 0.000 title claims abstract description 70
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 112
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 54
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 52
- 125000003118 aryl group Chemical group 0.000 claims abstract description 51
- 238000006880 cross-coupling reaction Methods 0.000 claims abstract description 47
- 238000007333 cyanation reaction Methods 0.000 claims abstract description 34
- 239000011701 zinc Substances 0.000 claims abstract description 27
- 239000000654 additive Substances 0.000 claims abstract description 25
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 24
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 230000000996 additive effect Effects 0.000 claims abstract description 17
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 17
- 239000011261 inert gas Substances 0.000 claims abstract description 11
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical group [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 144
- 238000006243 chemical reaction Methods 0.000 claims description 118
- 239000002904 solvent Substances 0.000 claims description 74
- 150000001875 compounds Chemical class 0.000 claims description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- 239000003446 ligand Substances 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 35
- 239000003054 catalyst Substances 0.000 claims description 32
- 239000002243 precursor Substances 0.000 claims description 26
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 17
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 17
- 230000008569 process Effects 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 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
- 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 claims description 13
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 13
- 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 12
- 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 claims description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 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
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 12
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 11
- 229910052751 metal Inorganic materials 0.000 claims description 11
- 239000002184 metal Substances 0.000 claims description 11
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 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 claims description 10
- 150000008282 halocarbons Chemical class 0.000 claims description 9
- 150000002825 nitriles Chemical class 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- 150000001408 amides Chemical class 0.000 claims description 8
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 8
- 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 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
- 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 8
- 125000004429 atom Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 229910052786 argon Inorganic materials 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-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
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 239000003849 aromatic solvent Substances 0.000 claims description 4
- UFZJUNYPYMYVIS-UHFFFAOYSA-N dicyclohexyl-(1-methyl-2-phenylindol-3-yl)phosphane Chemical compound C12=CC=CC=C2N(C)C(C=2C=CC=CC=2)=C1P(C1CCCCC1)C1CCCCC1 UFZJUNYPYMYVIS-UHFFFAOYSA-N 0.000 claims description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- HASCQPSFPAKVEK-UHFFFAOYSA-N dimethyl(phenyl)phosphine Chemical compound CP(C)C1=CC=CC=C1 HASCQPSFPAKVEK-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
- 125000001624 naphthyl group Chemical group 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
- 235000009518 sodium iodide Nutrition 0.000 claims description 4
- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical group [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 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
- 239000008096 xylene Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 6
- SBOQCPPINFMCBH-UHFFFAOYSA-N diphenylphosphane;methane Chemical compound C.C=1C=CC=CC=1PC1=CC=CC=C1.C=1C=CC=CC=1PC1=CC=CC=C1 SBOQCPPINFMCBH-UHFFFAOYSA-N 0.000 claims 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 51
- 239000000758 substrate Substances 0.000 abstract description 14
- 125000000524 functional group Chemical group 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000003197 catalytic effect Effects 0.000 abstract description 4
- 125000005228 aryl sulfonate group Chemical group 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 189
- 239000003208 petroleum Substances 0.000 description 58
- 239000000047 product Substances 0.000 description 56
- 239000007787 solid Substances 0.000 description 50
- 238000010898 silica gel chromatography Methods 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- 125000004093 cyano group Chemical group *C#N 0.000 description 21
- 238000004587 chromatography analysis Methods 0.000 description 18
- 229910052736 halogen Inorganic materials 0.000 description 16
- 150000002367 halogens Chemical class 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 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
- 238000004440 column chromatography Methods 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 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 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000011630 iodine Substances 0.000 description 7
- 229910052740 iodine Inorganic materials 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- 125000003367 polycyclic group Chemical group 0.000 description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 239000012039 electrophile Substances 0.000 description 6
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 150000008280 chlorinated hydrocarbons Chemical group 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
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- 238000012986 modification Methods 0.000 description 3
- 150000002989 phenols Chemical class 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- FRUBCADIVWBPBB-UHFFFAOYSA-N (4-acetylphenyl) methanesulfonate Chemical compound 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 compound COC1=CC=C(OS(C)(=O)=O)C=C1 BZKNVCHUULQHAT-UHFFFAOYSA-N 0.000 description 2
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 150000001499 aryl bromides Chemical class 0.000 description 2
- 150000001500 aryl chlorides Chemical class 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
- 150000001503 aryl iodides Chemical class 0.000 description 2
- 150000004696 coordination complex Chemical group 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- CRHWEIDCXNDTMO-UHFFFAOYSA-N ditert-butylphosphane Chemical compound CC(C)(C)PC(C)(C)C CRHWEIDCXNDTMO-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- 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 compound 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
- 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
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- TZHQWUAOIWRFSW-UHFFFAOYSA-N 4-bromo-2,6-difluorobenzonitrile Chemical compound FC1=CC(Br)=CC(F)=C1C#N TZHQWUAOIWRFSW-UHFFFAOYSA-N 0.000 description 1
- VSMDINRNYYEDRN-UHFFFAOYSA-N 4-iodophenol Chemical compound OC1=CC=C(I)C=C1 VSMDINRNYYEDRN-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
- 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
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- DQMYUSGNGHNAKG-UHFFFAOYSA-N P.N1C=CC2=CC=CC=C12 Chemical compound P.N1C=CC2=CC=CC=C12 DQMYUSGNGHNAKG-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 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
- 238000007259 addition reaction Methods 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
- DFNYGALUNNFWKJ-UHFFFAOYSA-N aminoacetonitrile Chemical compound NCC#N DFNYGALUNNFWKJ-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229960002708 antigout preparations Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 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
- 239000006227 byproduct Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 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
- 239000012018 catalyst precursor Substances 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000012295 chemical reaction liquid 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
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 229950004210 cromakalim Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000001004 diazonium dye Substances 0.000 description 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 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
- 230000000857 drug effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 229960002049 etravirine Drugs 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
- 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
- 238000007306 functionalization reaction Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000005984 hydrogenation 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
- 239000003112 inhibitor Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 231100001231 less toxic Toxicity 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
- 239000008204 material by function Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 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
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000010287 polarization 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
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 239000012041 precatalyst Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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 a preparation method of an aromatic nitrile or alkenyl nitrile compound. The preparation method of the invention comprises the following steps: under the protection of inert gas, in the presence of nickel complex, metallic zinc and additive, carrying out cross coupling reaction as shown below on aryl or heteroaryl sulfonate compound as shown in formula II and cyanation reagent, or carrying out cross coupling reaction as shown below on alkenyl sulfonate compound as shown in formula IV and cyanation reagent; wherein the additive is 4-Dimethylaminopyridine (DMAP), and the cyanating agent is zinc cyanide. The preparation method can simply and efficiently realize the cyanation of aryl sulfonate, heteroaryl sulfonate or alkenyl sulfonate by using a cheap catalytic system, has good functional group compatibility and substrate universality, and provides better application prospect and use value for realizing the industrial synthesis of aromatic nitrile or alkenyl nitrile compounds.
Description
Technical Field
The invention relates to the field of organic chemistry, in particular to a preparation method of an aromatic nitrile or alkenyl nitrile compound.
Background
As an excellent reaction intermediate in organic chemistry, aromatic nitrile compounds have been widely used in the fields of biology, medicine, pesticides, functional materials and the like. Such as 2, 4-dinitro-6-cyanoaniline is an important intermediate for the manufacture of excellent bright blue diazonium dyes; 4-bromo-2, 6-difluorobenzonitrile is an important synthetic intermediate for the synthesis of an excellent liquid crystal material with moderate dielectric anisotropy; meanwhile, many natural products and clinical medicines contain cyano groups, such as antitumor drugs Letrozole, beta inhibitor Bucindol, kinase inhibitor Neratinib, cardiovascular drug cromakalim, anti-HIV drug Etravirine, anti-gout drug Febuxostat, antidepressant drug Citalopram, diabetes drug alogliptin and the like. Cyano groups are widely used in pharmaceutical chemistry research, which is mainly determined by the particular nature of cyano groups. Cyano has a relatively small volume (about 1/8 of methyl), and in addition, the cyano has the characteristic of strong electron withdrawing property, so that the cyano becomes a good hydrogen bond acceptor and can penetrate deep into a target protein to form strong hydrogen bond interaction with key amino acid residues of an active site; meanwhile, the polarization degree of cyano groups is high, and polar interaction is promoted, so that the physical and chemical characteristics of the drug molecules can be changed by introducing cyano groups into the drug molecules, the interaction between the drug molecules and target proteins is enhanced, and the drug effect is improved; in addition, cyano groups have good metabolic stability and are biological electron emission bodies serving as functional groups such as hydroxyl groups, carboxyl groups and the like, and the characteristics make the cyano groups very important functional groups in pharmaceutical chemistry research. Currently, more than 30 cyano-containing drugs are marketed, and up to 20 cyano-containing drugs are under development.
The cyano group in the aromatic nitrile compound is also an important functional group, and can be converted into other functional groups through chemical reaction to form other important organic compounds, such as: the amide compound can be obtained through hydrogenation reduction; carboxylic acid compounds can be obtained by hydrolysis; primary amine compounds or aromatic aldehyde compounds can be obtained through reduction; tetrazole compounds can be obtained through addition reaction; carbonyl compounds can be obtained by nucleophilic addition.
In view of the unique nature and important role of cyano groups, the synthesis of cyano-containing compounds, particularly aromatic nitriles, has received great attention. The traditional method for synthesizing the aromatic nitrile is Rosenmund-von Braun reaction and Sandmeyer reaction, and the two methods need equivalent cuprous cyanide as cyanating reagent, so heavy metal pollution is caused, and the reaction generally needs higher temperature (150-250 ℃) and complicated post-treatment, thereby limiting the application of the two methods. The industrial preparation of aryl nitrile compounds is mainly carried out by ammoxidation, but the reaction is carried out at high temperature and high pressure, and the use of ammonia in large excess is limited to cyanation of toluene and its derivatives and picoline and its derivatives, thereby limiting the application of the process. Therefore, the method for cyanation is developed mildly and efficiently, accords with the development trend of green chemical industry, meets the requirements of rapid development in various related fields such as social production of medicines, materials and the like, and is particularly urgent and needed.
The transition metal catalyzed cross-coupling reaction is one of the effective methods of constructing carbon-carbon bonds, and the transition metal catalyzed cross-coupling reaction of electrophiles with metal cyanide compounds can be used to effectively form aromatic nitriles. The task group of Takagi reported for the first time that palladium-catalyzed coupling of aryl iodides or aryl bromides with potassium cyanide (Takagi, k.; okamoto, t.; sakakiba, y.; oka, s.chem. Lett.1973, 471), while only limited substrates in this paper could achieve cyanation, it is this pioneering work that, in the next decades, transition metal-catalyzed cyanation reactions have been extensively studied and developed, and a range of low-toxicity cyanation reagents have been developed, such as: TMSCN, zn (CN) 2 、K 4 Fe(CN) 6 Acetone cyanohydrin, NCTS, etc. Aryl iodides and aryl bromides are often used as electrophiles in such reactions due to their relatively high reactivity. Relatively widely available aryl chloride compounds have low activity due to the high C-Cl bond energy and have rarely been used as electrophiles in earlier studies. However, aryl chlorides have also been increasingly used in metal-catalyzed cyanation reactions in recent years through the development of novel ligands and catalytic systems. However, there are significant disadvantages to using halogenated hydrocarbons as electrophiles: organic halides have a certain harm to the environment due to their own toxicity; secondly, aryl halide generates a halogen-containing byproduct after the coupling reaction; and aryl halides are not readily available directly. Therefore, there is an urgent need to develop more environmentally friendly and green electrophiles to synthesize aromatic nitriles.
Through literature research, the phenolic compounds have the advantages of wide sources, low price, environmental friendliness and the like, and are gradually applied to cross coupling reactions. Meanwhile, due to the difficulty in breaking the C-O bond of the phenol, the phenolic compound is converted into a phenolic derivative, so that progressive functionalization of the substrate can be realized. Therefore, the application of the phenol derivative as the electrophile in the coupling reaction has important research significance. In recent years, few cyanation reactions have been reported using transition metal catalyzed phenolic derivatives. In 1989, the Widdowson task group was first reportedThe coupling reaction of nickel catalyzed aryl triflate and potassium cyanide is performed to synthesize a series of aromatic nitrile compounds. The Percec group subsequently further developed a nickel-catalyzed coupling reaction of aryl mesylate with potassium cyanide. However, in this reaction, highly toxic potassium cyanide is required as the cyanating reagent, and in addition, when steric hindrance exists in the ortho position of the substrate, the reaction yield is low, for example, when the substrate is 2,4, 6-trimethylphenyl trifluoromethanesulfonate as the substrate, the reaction yield is 32%. (ref: 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.). Subsequently, the Neumeyer group and the Fairfax group report palladium-catalyzed cyanation of aryl triflates using zinc cyanide as the cyanide source, which is relatively less toxic, but at temperatures as high as 140℃to 200℃as required. (ref: zhang, a.; neumeeyer, 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, the Kwong group reports that the potassium ferricyanate (K 4 [Fe(CN) 6 ]·3H 2 O) is a cyanogen source, palladium catalyzes the coupling reaction of aryl methane sulfonate or aryl p-toluenesulfonate under mild conditions, and indole phosphine ligand CM-phos with special electronic effect and steric effect, which is developed by the group, needs to be added in the reaction, and the ligand has special structure and is relatively expensive. (reference Yeung, p.y.; so, c.m.; lau, c.p.; kwong, f.y. Angelw.chem.int.ed.2010, 49,8918.). In 2016, yamaguchi reported that nickel catalyzed cyanation of aryl carbamates or aryl pivalates with aminoacetonitrile as the cyanide source required the use of highly sterically hindered, rich dcype or dcypt as the ligand and required temperatures up to 150℃limiting the utility of the reaction (ref: takise, R.; iami, K.; yamaguchi, J. Org. Lett.2016,18,4428.). In view of the limitations of the above-mentioned transition metal-catalyzed cyanation of phenolic derivatives, such as the need for special phosphine ligands, complicated operations (pre-catalyst preparation) and post-treatments, special catalyst precursors and higher reaction temperatures and longer reaction timesInter-space, etc.
Therefore, the research and development of a more efficient, simple and mild cyanation method of sulfonate compounds catalyzed by cheap catalysts such as nickel and cheap ligands are urgent and needed, and a better application prospect is provided for realizing the industrial synthesis of aromatic nitrile or alkenyl nitrile compounds.
Disclosure of Invention
The invention aims to overcome the defects of high price of a catalyst and a ligand, poor compatibility of functional groups, poor universality of substrates and the like of the traditional preparation method of the aromatic nitrile or alkenyl nitrile compound, and provides the preparation method of the aromatic nitrile or alkenyl nitrile compound. The preparation method can simply and efficiently implement cyanation of aryl sulfonate, heteroaryl sulfonate or alkenyl sulfonate by using a cheap catalytic system, and has good functional group compatibility and substrate universality.
The invention solves the technical problems through the following technical proposal.
The invention provides a preparation method of an aromatic nitrile compound shown in a formula I, which comprises the following steps: under the protection of inert gas, in the presence of nickel complex, metallic zinc and additive, carrying out cross coupling reaction as shown below on aryl or heteroaryl sulfonate compound as shown in formula II and cyanation reagent; wherein the additive is 4-Dimethylaminopyridine (DMAP), and the cyanation reagent is zinc cyanide;
in the aromatic nitrile compound shown in the formula I and the aryl or heteroaryl sulfonate compound shown in the formula II,
n is selected from any integer between 0- [ M-1], wherein M represents the maximum number of substitutions on the ring alpha, e.g., n may be 0, 1 or 2.
R 1 Which may be the same or different, are each independently selected from halogen, C 1 -C 6 Straight OR branched alkoxy, -CN, -C (=o) OR a 、-NR b R c 、-C(＝O)R d 、-C(＝O)NR e R f 、R g Substituted C 3 -C 10 Aryl or heteroaryl, R h Substituted C 1 -C 6 Straight or branched alkyl of (a); wherein R is a 、R b 、R c 、R d 、R e 、R f 、R g And R is h Each independently selected from-H, halogen, -OH, -CN, C 1 -C 4 Straight-chain or branched alkoxy and C 1 -C 4 One or more of a linear or branched alkyl group; wherein the halogen is preferably fluorine, chlorine, bromine or iodine; the C is 1 -C 4 Preferably C 1 -C 3 Further preferred is methoxy, ethoxy, propoxy or isopropoxy; the C is 1 -C 4 Is preferably C 1 -C 3 Further preferred is methyl, ethyl, propyl or isopropyl.
Alternatively, any two adjacent substituted R' s 1 (when n>When =2) together with the atoms of the ring α to which they are each attached form a carbocycle or carbocycle which is fused to the ring α, said carbocycle or carbocycle being a 3-10 membered ring, said carbocycle containing 1-4 heteroatoms selected from O, N and S.
When R is 1 In the case of halogen, the halogen is preferably fluorine, chlorine, bromine or iodine.
When R is 1 Is C 1 -C 6 When straight or branched alkoxy, said C 1 -C 6 Preferably C 1 -C 3 Further preferred are methoxy, ethoxy, propoxy or isopropoxy groups.
When R is 1 is-C (=O) OR a When R is a Preferably C 1 -C 4 Further preferred is methyl, ethyl, propyl or isopropyl.
When R is 1 is-NR b R c When R is b And R is c Each independently is preferably C 1 -C 4 Further preferred is methyl, ethyl, propyl or isopropyl.
When R is 1 is-C (=O) R d When R is d Preferably C 1 -C 4 Further preferred is methyl, ethyl, propyl or isopropyl.
When R is 1 is-C (=O) NR e R f When R is e And R is f Each independently is preferably C 1 -C 4 Further preferred is methyl, ethyl, propyl or isopropyl.
When R is 1 Is R g Substituted C 3 -C 10 In the case of aryl or heteroaryl groups of (C) 3 -C 10 Preferably phenyl or thienyl;
when R is 1 Is R h Substituted C 1 -C 6 In the case of a linear or branched alkyl group, said C 1 -C 6 Is preferably C 1 -C 3 Further preferred is methyl, ethyl, propyl or isopropyl.
When any two adjacent substituted R' s 1 (when n>When =2) together with the atoms of the ring α to which they are each attached form a carbocycle or carbocycle which is fused to the ring α, said carbocycle or carbocycle preferably being a 3-5 membered ring, said carbocycle containing 1 or 2 heteroatoms selected from O, N and S.
When n is 1, R 1 Further preferred are methyl, n-butyl, methoxy, amino, acetyl, methoxycarbonyl, ethoxycarbonyl, cyano and phenyl.
When n is 2, R 1 Which may be the same or different, are further each independently preferably selected from methyl or methoxy; or two R 1 Together with the atoms of the ring alpha to which they are each attached form a dioxolyl group.
-OS(＝O) 2 R is conventional in the artThe sulfonate structure which can be used as a good leaving group, wherein R is selected from halogen, C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight-chain or branched haloalkyl, or R i Substituted phenyl, R i Selected from halogen (e.g. fluorine, chlorine, bromine or iodine), C 1 -C 6 Straight or branched alkyl (preferably C) 1 -C 3 Further preferably methyl, ethyl, propyl or isopropyl), or-NR j R k (R j And R is k Each independently selected from C 1 -C 4 Further preferred are methyl, ethyl, propyl or isopropyl groups).
When R is halogen, the halogen is preferably fluorine, chlorine, bromine or iodine.
When R is C 1 -C 6 In the case of a linear or branched alkyl group, said C 1 -C 6 Preferably C 1 -C 3 Further preferred is methyl, ethyl, propyl or isopropyl.
When R is C 1 -C 6 In the case of a straight-chain or branched haloalkyl group, said C 1 -C 6 Preferably C 1 -C 3 Further preferably a trifluoromethyl group.
In the present invention, the-OS (=O) 2 R is preferably any one of the following structures: fluorosulfonyl (-SO) 2 F) Trifluoromethyl sulfonyl (-Tf), methylsulfonyl (-Ms), p-toluenesulfonyl (-Ts) or sulfamoyl (-SO) 2 NMe 2 )。
In the invention, in the aromatic nitrile compound shown in the formula I and the aryl or heteroaryl sulfonate compound shown in the formula II, the ring alpha is an aromatic ring or an aromatic heterocycle.
Wherein when said ring α is an aromatic ring, said aromatic ring refers to any stable monocyclic or polycyclic carbocycle of up to 6 atoms in each ring, said polycyclic ring may be of bi-, tri-or tetra-cyclic and wherein at least one ring is an aromatic ring; when saidWhen the aromatic ring is polycyclic and a non-aromatic ring is present therein, -OS (=o) 2 The connection of R and-CN is respectively carried out through an aromatic ring; and n are the same or different R 1 The connection thereto is not limited in any way.
Wherein, when the ring α is an aromatic heterocycle, the aromatic heterocycle refers to any stable single ring or multiple rings of up to 6 atoms in each ring, the multiple rings may be bi-, tri-or tetra-cyclic and wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from O, N and S. When the aromatic heterocycle is polycyclic and wherein a non-aromatic ring is present or contains no heteroatoms, -OS (=o) 2 The connection of R and-CN to each of them is made via a "heteroatom-containing aromatic ring"; and n are identical or different-R 1 The connection thereto is not limited in any way.
In the present invention, the aromatic ring is preferably a monocyclic aromatic ring or a bicyclic condensed ring aromatic ring, such as a benzene ring or a naphthalene ring.
In the present invention, the aromatic heterocycle is preferably a monocyclic pyridine ring or a bicyclic quinoline ring.
In the invention, the aryl or heteroaryl sulfonate compound shown in the formula II and the aromatic nitrile compound shown in the formula I are more preferably any one pair of compounds as follows:
In the preparation method of the aromatic nitrile compound shown in the formula I, the cross-coupling reaction is carried out under an inert gas protection system, and the inert gas can be one or more of nitrogen, helium, argon and neon.
In the preparation method of the aromatic nitrile compound shown in the formula I, the dosage of the additive DMAP can be conventionally used in the field; the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to DMAP is preferably 1:0.1-1:10, and more preferably 1:1-1:1.5.
In the preparation method of the aromatic nitrile compound shown in the formula I, other additives can be added besides the additive DMAP, and the other additives are quaternary ammonium salts and/or inorganic salts; wherein the quaternary ammonium salt is preferably tetraethylammonium iodide; the inorganic salt is preferably one or more of sodium iodide, potassium iodide and lithium iodide, more preferably potassium iodide.
In the preparation method of the aromatic nitrile compound shown in the formula I, when the reaction system also comprises quaternary ammonium salt and/or inorganic salt, the dosage of the quaternary ammonium salt and/or inorganic salt can be used conventionally in the field; the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the quaternary ammonium salt and/or the inorganic salt is preferably 1:0.1-1:10, more preferably 1:0.5-1:1.
In the preparation method of the aromatic nitrile compound shown in the formula I, the dosage of the metal zinc can be used conventionally in the field of such reactions; the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the metal zinc is preferably 1:0.01-1:10, more preferably 1:0.1-1:1, and even more preferably 1:0.2-1:0.4.
In the preparation method of the aromatic nitrile compound shown in the formula I, the nickel complex can be conventionally used in the cross-coupling reaction in the field, and can be reacted with a metal complex form of a conventional applicable ligand of the conventional applicable nickel precursor catalyst which is well known in the field, and other ligands can be not added any more at the moment; the conventionally-applicable nickel precursor catalyst well known in the art and its conventionally-applicable ligand can also be coordinated in situ in the reaction system to participate in the reaction. The nickel complex of the invention is preferably NiBr 2 (PPh 3 ) 2 And/or NiCl 2 (dppf); alternatively, the nickel precursor catalyst of the present invention is preferably selected from Ni (cod) 2 、NiCl 2 、NiBr 2 、NiI 2 、NiBr 2 (diglyme)、NiCl 2 (glyme)、NiBr 2 (DME)、NiF 2 And NiCl 2 ·6H 2 One or more of O; for example NiBr 2 (DME)、NiI 2 And NiCl 2 ·6H 2 One or more of O.
In the preparation method of the aromatic nitrile compound shown in the formula I, the dosage of the nickel complex can be used conventionally in the reaction of the field; the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the nickel complex is preferably 1:0.01-1:1, more preferably 1:0.02-1:0.50, and even more preferably 1:0.05-1:0.10.
The preparation method of the aromatic nitrile compound shown in the formula I further comprises the conventional applicable ligand which can be the conventional ligand applicable to nickel catalysts in the cross coupling reaction in the field and can be selected from triphenylphosphine (PPh) 3 ) Triethylphosphine, tributylphosphine (TBUP), tricyclohexylphosphine (TCHP), bis-diphenylphosphinomethane (dppm), dimethylphenylphosphine (PMe) 2 Ph), diphenylmethylphosphine (PMePh) 2 ) 1, 2-bis (diphenylphosphine) ethane (dppe), 1, 3-bis (diphenylphosphine) propane (dppp), 1, 4-bis (diphenylphosphine) butane (dppb), 1' -bis (diphenylphosphine) ferrocene (dppf), 9-dimethyl-4, 5-bis-diphenylphosphine xanthene (xantphos), 4, 5-bis (di-t-butylphosphine) -9, 9-dimethyl xanthene ] t One or more of Bu-xantphos) and 3- (dicyclohexylphosphino) -1-methyl-2-phenyl-1H-indole (CM-phos), more preferably bis-diphenylphosphinomethane (dppm), diphenylmethylphosphine (PMePH) 2 ) One or more of 1, 2-bis (diphenylphosphine) ethane (dppe), 1, 3-bis (diphenylphosphine) propane (dppp), 1, 4-bis (diphenylphosphine) butane (dppb), 1' -bis (diphenylphosphine) ferrocene (dppf), and 9, 9-dimethyl-4, 5-bis-diphenylphosphine xanthenes (xantphos); for example diphenylmethylphosphine, 1' -bis (diphenylphosphino) ferrocene and 9, 9-dimethyl-4, 5-bisdiphenylphosphino xanthene One or more of the following.
In the preparation method of the aromatic nitrile compound shown in the formula I, the reaction system also comprises the conventional applicable ligand, and the molar ratio of the nickel precursor catalyst to the ligand can be used conventionally in the cross coupling reaction in the field. The molar ratio of the present invention is preferably 1:1 to 1:10, more preferably 1:1 to 1:5, still more preferably 1:1.2.
In the preparation method of the aromatic nitrile compound shown in the formula I, the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the cyanation reagent can be the conventional molar ratio of the reaction in the field; the present invention is preferably 1:0.1 to 1:10, more preferably 1:0.5 to 1:2, still more preferably 1:0.6 to 1:1.2, for example 1:0.8.
In the preparation method of the aromatic nitrile compound shown in the formula I, the solvent can be conventionally used in the cross coupling reaction in the field and does not participate in the reaction; the invention preferably selects one or more of an aromatic hydrocarbon solvent, an ether solvent, a halogenated hydrocarbon solvent, a nitrile solvent, an amide solvent and a sulfoxide solvent; the aromatic solvent is preferably one or more of benzene, toluene and xylene; the ether solvent is preferably one or more of diethyl ether, 1, 4-dioxane and tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably one or more of dichloromethane, dichloroethane and chloroform; the nitrile solvent is preferably acetonitrile; the amide solvent is preferably one or more of N, N-dimethylformamide, N-Dimethylacetamide (DMA) and hexamethylphosphoramide; the sulfoxide solvent is preferably dimethyl sulfoxide. The solvent is more preferably one or more of acetonitrile, N-dimethylformamide and N, N-dimethylacetamide.
In the preparation method of the aromatic nitrile compound shown in the formula I, the dosage of the solvent can be conventionally used in the cross coupling reaction in the field; the molar volume ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the solvent is preferably 0.01mmol/mL-1mmol/mL, more preferably 0.1mmol/mL-0.5mmol/mL.
In the preparation method of the aromatic nitrile compound shown in the formula I, the reaction temperature of the cross-coupling reaction can be conventionally used in the cross-coupling reaction in the field; the temperature in the present invention may be-100℃to 500℃preferably 0℃to 150℃more preferably 50℃to 100℃and still more preferably 60℃to 80 ℃.
In the preparation method of the aromatic nitrile compound shown in the formula I, the reaction progress of the cross-coupling reaction can be monitored by adopting a conventional monitoring method (such as TLC, HPLC or NMR) used in the cross-coupling reaction in the field, and the reaction end point is generally the moment when the aryl or heteroaryl sulfonate compound shown in the formula II disappears or is no longer reacted.
In the preparation method of the aromatic nitrile compound shown in the formula I, the reaction time of the cross-coupling reaction can be conventionally used in the field of the cross-coupling reaction; in the present invention, it is preferably 0.1 to 200 hours, more preferably 3 to 12 hours.
In the preparation method of the aromatic nitrile compound shown in the formula I, after the cross-coupling reaction is finished, the preparation method preferably further comprises the following post-treatment steps: after the reaction is finished, filtering, removing the solvent, and separating by column chromatography to obtain the target compound, wherein the column chromatography can be performed by adopting a conventional method of the operation in the field. The eluent is preferably a mixed solvent of an alkane solvent and an ester solvent. Wherein the volume ratio of the alkane solvent to the ester solvent is preferably 100:1-1:1; the alkane solvent is preferably petroleum ether; the ester solvent is preferably ethyl acetate.
The invention also provides a preparation method of the alkenyl nitrile compound shown in the formula III, which comprises the following steps: under the protection of inert gas, in the presence of nickel complex, metallic zinc and additive, carrying out cross coupling reaction as shown in IV on alkenyl sulfonate compound and cyanation reagent; wherein the additive is 4-Dimethylaminopyridine (DMAP); the cyanation reagent is zinc cyanide;
wherein, -OS (=o) 2 R is a sulfonate structure as conventionally described in the art as a good leaving group, the definition of which is as described previously, namely: r is selected from halogen, C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight-chain or branched haloalkyl, or R i Substituted phenyl, R i Selected from halogen (e.g. fluorine, chlorine, bromine or iodine), C 1 -C 6 Straight or branched alkyl (preferably C) 1 -C 3 Further preferably methyl, ethyl, propyl or isopropyl), or-NR j R k (R j And R is k Each independently selected from C 1 -C 4 Further preferred are methyl, ethyl, propyl or isopropyl groups).
When R is halogen, the halogen is preferably fluorine, chlorine, bromine or iodine.
When R is C 1 -C 6 In the case of a linear or branched alkyl group, said C 1 -C 6 Preferably C 1 -C 3 Further preferred is methyl, ethyl, propyl or isopropyl.
When R is C 1 -C 6 In the case of a straight-chain or branched haloalkyl group, said C 1 -C 6 Preferably C 1 -C 3 Further preferably a trifluoromethyl group.
In the present invention, the-OS (=O) 2 R is preferably any one of the following structures: fluorosulfonyl (-SO) 2 F) Trifluoromethyl sulfonyl (-Tf), methylsulfonyl (-Ms), p-toluenesulfonyl (-Ts) or sulfamoyl (-SO) 2 NMe 2 )。
In the alkenyl nitrile compound shown in the formula III and the alkenyl sulfonate compound shown in the formula IV, R 2 、R 3 And R is 4 Each independently selected from-H, - (CH) 2 )x-R m Substituted C 3 -C 10 Or R is aryl or heteroaryl n Substituted C 1 -C 6 Straight or branched alkyl of (a); wherein R is m And R is n Each independently selected from-H, halogen, -OH, -CN, C 1 -C 4 Straight-chain or branched alkoxy and C 1 -C 4 One or more of a linear or branched alkyl group; wherein the halogen is preferably fluorine, chlorine, bromine or iodine; the C is 1 -C 4 Preferably C 1 -C 3 Further is methoxy, ethoxy, propoxy or isopropoxy; the C is 1 -C 4 Is preferably C 1 -C 3 Further preferably methyl, ethyl, propyl or isopropyl; x is selected from any integer between 0 and 4, such as 0, 1, 2 or 3.
Wherein said- (CH) 2 )x-R m Substituted C 3 -C 10 The C is aryl or heteroaryl 3 -C 10 Preferably C 6 -C 10 Such as phenyl or naphthyl.
Wherein R is as follows n Substituted C 1 -C 6 In the linear or branched alkyl group of (C) 1 -C 6 Is preferably C 1 -C 3 Further preferred is methyl, ethyl, propyl or isopropyl.
Alternatively, R 2 And R is R 3 Or R 2 And R is R 4 Together forming a 5-10 membered monocyclic or polycyclic carbocycle or carbocycle containing 1-4 heteroatoms selected from O, N and S; the 5-to 10-membered monocyclic or polycyclic carbocycle or carbocycle may be a saturated or semi-saturated ring; and it may be further substituted by R n And (3) substitution.
Wherein the 5-10 membered monocyclic or polycyclic carbocycle is preferably a monocyclic or bicyclic carbocycle, and further preferably cyclohexene or benzocyclohexene.
In the invention, the alkenyl nitrile compound shown in the formula III and the alkenyl sulfonate compound shown in the formula IV can be Z-type and/or E-type, and the alkenyl nitrile compound and the alkenyl sulfonate compound are not limited in any way.
In the invention, the alkenyl sulfonate compound shown in the formula IV and the alkenyl nitrile compound shown in the formula III are more preferably any one pair of compounds as follows:
in the present invention, unless the substrate is different, the reaction parameters and conditions used in the preparation method of the alkenyl nitrile compound shown in the formula III are the same as those described above, namely:
in the preparation method of the alkenyl nitrile compound shown in the formula III, the cross-coupling reaction is carried out under an inert gas protection system, and the inert gas can be one or more of nitrogen, helium, argon and neon.
In the preparation method of the alkenyl nitrile compound shown in the formula III, the dosage of the additive DMAP can be conventional in the field; the molar ratio of the alkenyl sulfonate compound shown in the formula IV to DMAP is preferably 1:0.1-1:10, and more preferably 1:1-1:1.5.
In the preparation method of the alkenyl nitrile compound shown in the formula III, other additives can be added besides the additive DMAP, and the other additives are quaternary ammonium salts and/or inorganic salts; wherein the quaternary ammonium salt is preferably tetraethylammonium iodide; the inorganic salt is preferably one or more of sodium iodide, potassium iodide and lithium iodide, more preferably potassium iodide.
In the preparation method of the alkenyl nitrile compound shown in the formula III, when the reaction system also comprises quaternary ammonium salt and/or inorganic salt, the dosage of the quaternary ammonium salt and/or inorganic salt can be used conventionally in the field; the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the quaternary ammonium salt and/or the inorganic salt is preferably 1:0.1-1:10, more preferably 1:0.5-1:1.
In the preparation method of the alkenyl nitrile compound shown in the formula III, the dosage of the metal zinc can be used conventionally in the reaction in the field; the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the metal zinc is preferably 1:0.01-1:10, more preferably 1:0.1-1:1, and even more preferably 1:0.2-1:0.4.
In the preparation method of the alkenyl nitrile compound shown in the formula III, the nickel complex can be conventionally used in the cross coupling reaction in the field, and can be reacted with a metal complex form of a conventionally applicable ligand of the conventionally applicable nickel precursor catalyst which is well known in the field, and other ligands can be not added any more; the conventionally-applicable nickel precursor catalyst well known in the art and its conventionally-applicable ligand can also be coordinated in situ in the reaction system to participate in the reaction. The nickel complex is preferably NiBr 2 (PPh 3 ) 2 And/or NiCl 2 (dppf); alternatively, the nickel precursor catalyst of the present invention is preferably selected from Ni (cod) 2 、NiCl 2 、NiBr 2 、NiI 2 、NiBr 2 (diglyme)、NiCl 2 (glyme)、NiBr 2 (DME)、NiF 2 And NiCl 2 ·6H 2 One or more of O; for example NiBr 2 (DME)、NiI 2 And NiCl 2 ·6H 2 One or more of O.
In the preparation method of the alkenyl nitrile compound shown in the formula III, the dosage of the nickel complex can be used conventionally in the reaction of the field; the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the nickel complex is preferably 1:0.01-1:1, more preferably 1:0.02-1:0.50, and even more preferably 1:0.05-1:0.10.
The preparation method of the alkenyl nitrile compound shown in the formula III further comprises the conventional applicable ligand which can be the conventional ligand applicable to nickel catalysts in the cross coupling reaction in the field and can be selected from triphenylphosphine (PPh) 3 ) Triethylphosphine, tributylphosphine (TBUP), tricyclohexylphosphine (TC)HP), bis-diphenylphosphinomethane (dppm), dimethylphenylphosphine (PMe) 2 Ph), diphenylmethylphosphine (PMePh) 2 ) 1, 2-bis (diphenylphosphine) ethane (dppe), 1, 3-bis (diphenylphosphine) propane (dppp), 1, 4-bis (diphenylphosphine) butane (dppb), 1' -bis (diphenylphosphine) ferrocene (dppf), 9-dimethyl-4, 5-bis-diphenylphosphine xanthene (xantphos), 4, 5-bis (di-t-butylphosphine) -9, 9-dimethyl xanthene ] t One or more of Bu-xantphos) and 3- (dicyclohexylphosphino) -1-methyl-2-phenyl-1H-indole (CM-phos), more preferably bis-diphenylphosphinomethane (dppm), diphenylmethylphosphine (PMePH) 2 ) One or more of 1, 2-bis (diphenylphosphine) ethane (dppe), 1, 3-bis (diphenylphosphine) propane (dppp), 1, 4-bis (diphenylphosphine) butane (dppb), 1' -bis (diphenylphosphine) ferrocene (dppf), and 9, 9-dimethyl-4, 5-bis-diphenylphosphine xanthenes (xantphos); such as one or more of diphenylmethylphosphine, 1' -bis (diphenylphosphino) ferrocene, and 9, 9-dimethyl-4, 5-bis-diphenylphosphino xanthene.
In the preparation method of the alkenyl nitrile compound shown in the formula III, the reaction system also comprises the conventional applicable ligand, and the molar ratio of the nickel precursor catalyst to the ligand can be used conventionally in the cross coupling reaction in the field. The molar ratio of the present invention is preferably 1:1 to 1:10, more preferably 1:1 to 1:5, still more preferably 1:1.2.
In the preparation method of the alkenyl nitrile compound shown in the formula III, the mol ratio of the alkenyl sulfonate compound shown in the formula IV to the cyanation reagent can be the mol ratio which is conventional in the reaction in the field; the present invention is preferably 1:0.1 to 1:10, more preferably 1:0.5 to 1:2, still more preferably 1:0.6 to 1:1.2, for example 1:0.8.
In the preparation method of the alkenyl nitrile compound shown in the formula III, the solvent can be conventionally used in the cross coupling reaction in the field and does not participate in the reaction; the invention preferably selects one or more of an aromatic hydrocarbon solvent, an ether solvent, a halogenated hydrocarbon solvent, a nitrile solvent, an amide solvent and a sulfoxide solvent; the aromatic solvent is preferably one or more of benzene, toluene and xylene; the ether solvent is preferably one or more of diethyl ether, 1, 4-dioxane and tetrahydrofuran; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably one or more of dichloromethane, dichloroethane and chloroform; the nitrile solvent is preferably acetonitrile; the amide solvent is preferably one or more of N, N-dimethylformamide, N-Dimethylacetamide (DMA) and hexamethylphosphoramide; the sulfoxide solvent is preferably dimethyl sulfoxide. The solvent is more preferably one or more of acetonitrile, N-dimethylformamide and N, N-dimethylacetamide.
In the preparation method of the alkenyl nitrile compound shown in the formula III, the dosage of the solvent can be conventionally used in the cross coupling reaction in the field; the molar volume ratio of the alkenyl sulfonate compound shown in the formula IV to the solvent is preferably 0.01mmol/mL-1mmol/mL, more preferably 0.1mmol/mL-0.5mmol/mL.
In the preparation method of the alkenyl nitrile compound shown in the formula III, the reaction temperature of the cross-coupling reaction can be conventionally used in the field of the cross-coupling reaction; the temperature in the present invention may be-100℃to 500℃preferably 0℃to 150℃more preferably 50℃to 100℃and still more preferably 60℃to 80 ℃.
In the preparation method of the alkenyl nitrile compound shown in the formula III, the reaction progress of the cross-coupling reaction can be monitored by adopting a conventional monitoring method (such as TLC, HPLC or NMR) used in the cross-coupling reaction in the field, and the reaction end point is generally when the alkenyl sulfonate compound shown in the formula IV disappears or is no longer reacted.
In the preparation method of the alkenyl nitrile compound shown in the formula III, the reaction time of the cross-coupling reaction can be conventionally used in the field of the cross-coupling reaction; in the present invention, it is preferably 0.1 to 200 hours, more preferably 3 to 12 hours.
In the preparation method of the alkenyl nitrile compound shown in the formula III, after the cross-coupling reaction is finished, the preparation method preferably further comprises the following post-treatment steps: after the reaction is finished, filtering, removing the solvent, and separating by column chromatography to obtain the target compound, wherein the column chromatography can be performed by adopting a conventional method of the operation in the field. The eluent is preferably a mixed solvent of an alkane solvent and an ester solvent. Wherein the volume ratio of the alkane solvent to the ester solvent is preferably 100:1-1:1; the alkane solvent is preferably petroleum ether; the ester solvent is preferably ethyl acetate.
The invention further provides an aromatic nitrile compound shown in the formula I or an alkenyl nitrile compound shown in the formula III,
wherein each substituent is as defined above.
Specifically, the invention also provides an aromatic nitrile or alkenyl nitrile compound shown in the following structure:
the above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the invention realizes the cyanation reaction of aryl sulfonate, heteroaryl sulfonate or alkenyl sulfonate by using a simple and easily obtained catalytic system, has the advantages of simple operation, high reaction efficiency, mild condition, good functional group compatibility and substrate universality, and the like, and provides better application prospect and use value for realizing the industrial synthesis of aromatic nitrile or alkenyl nitrile compounds.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Preparation example 1:
the general preparation process comprises the following steps: adding p-iodophenol (1 equiv), boric acid (1.2 equiv) and 5% Pd/CaCO into round bottom bottle 3 (1.5mol％),K 2 CO 3 (2 equiv), etOH and water were dissolved, heated to 80deg.C and refluxed and the reaction detected by TLC. Returning to room temperature, filtering with diatomite to remove precipitate, quenching with saturated common salt water, extracting with ethyl acetate, washing the organic phase with water, washing with saturated common salt water, drying with anhydrous magnesium sulfate, filtering, concentrating, and separating and purifying.
Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate/dichloromethane=8:1:1 to pure dichloromethane, product as white solid 1.81g, 91% yield. m.p=81.0-82.9 ℃. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):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 C 13 H 13 O 2 [M+H] + :201.0910,found 201.0910.
Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate/dichloromethane=6:1:1 to petroleum ether/dichloromethane=1:1, then recrystallized from dichloromethane/n-hexane to give 1.09g of white solid with 62% yield. m.p=172.4-174.2 ℃. 1 H NMR(400MHz,DMSO-d 6 ):δ6.81(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). 13 C NMR(100MHz,DMSO-d 6 ):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 C 10 H 8 OS[M] + :176.0296,found 176.0295.
Preparation example 2:
dissolving phenol (1 equiv) in ethyl acetate in round bottom bottle, adding Et under ice water bath 3 N (2 equiv), msCl (1.3 equiv), after addition was complete, the ice-water bath was removed, and the reaction was completed by TLC at room temperature. Adding water to quench the reaction, extracting with ethyl acetate, washing the organic phase with water, drying with anhydrous magnesium sulfate, filtering with silica gel, concentrating the filtrate, and separating and purifying.
Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=4:1, the product was a pale yellow liquid in 98% yield. 1 H NMR(400MHz,CDCl 3 ):δ0.93(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). 13 C NMR(100MHz,CDCl 3 ):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 C 11 H 20 NO 3 S[M+NH 4 ] + :246.1158,found 246.1157.
Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetateDichloromethane = 4:1:1, product as white solid in 94% yield. m.p=53.8-55.1 ℃. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):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 C 9 H 16 NO 4 S[M+NH 4 ] + :234.0794,found 234.0792.
The dichloromethane/n-hexane was recrystallized, the product was a white solid in 89% yield. m.p=148.6-149.7 ℃. 1 H NMR(400MHz,CDCl 3 ):δ2.39(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). 13 C NMR(100MHz,CDCl 3 ):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 C 14 H 18 NO 3 S[M+NH 4 ] + :280.1002,found 280.0998.
The dichloromethane/n-hexane was recrystallized, the product was a white solid with a yield of 95%. m.p=83.4-85.0 ℃. 1 H NMR(400MHz,CDCl 3 ,Me 4 Si):δ3.16(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). 13 C NMR(100MHz,CDCl 3 ,Me 4 Si):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 C 14 H 18 NO 4 S[M+NH 4 ] + :296.0951,found 296.0948.
Silica gel column chromatography, methylene dichloride/normal hexane recrystallization, and the product is white solid with the yield of 95 percent. m.p=120.8-122.2 ℃. 1 H NMR(400MHz,DMSO-d 6 ):δ7.27-7.31(m,2H),7.45(d,J＝8.0Hz,2H),7.69-7.75(m,4H). 13 C NMR(100MHz,DMSO-d 6 ):δ37.40,115.79( 2 J C-F ＝21.3Hz),122.73,128.33,128.83( 3 J C-F ＝7.5Hz),135.38( 4 J C-F ＝3.8Hz),138.31,148.56,162.08( 1 J C-F ＝242.9Hz). 19 F NMR(376.1MHz,DMSO-d 6 ):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 C 13 H 15 FNO 3 S[M+NH 4 ] + :284.0751,found 284.0750.
The dichloromethane/n-hexane was recrystallized and the product was a white solid in 84% yield. m.p=160.8-162.2 ℃. 1 H NMR(400MHz,DMSO-d 6 ):δ3.41(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). 13 C NMR(100MHz,DMSO-d 6 ):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 C 11 H 14 NO 3 S 2 [M+NH 4 ] + :272.0410,found272.0410.
Preparation example 3:
paraformaldehyde phenol (1.22 g,10 mmol) in a round bottom flask was dissolved in 30mL of ethyl acetate and Et added at 0deg.C 3 N (2.8 mL,20 mmol), msCl (1.0 mL,13 mmol), after the addition was completed, the ice-water bath was removed, and the reaction was completed by TLC at room temperature. Adding water to quench the reaction, extracting with ethyl acetate, washing the organic phase with water, washing with saturated saline, drying with anhydrous magnesium sulfate, filtering with silica gel, concentrating the filtrate, and performing the next reaction.
The product of the above step was dissolved in 20mL MeOH and 20mL DCM, and NaBH was added in portions 4 (491.8 mg,13 mmol) and after the addition was complete, the reaction was completed by TLC. The reaction was quenched by addition of saturated ammonium chloride, extracted with DCM, washed with organic phase, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, chromatographed on silica gel column, eluting with eluent: petroleum ether/ethyl acetate=4:1, separated to give 1.899g of colorless liquid with a yield of 95%. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):δ37.21,64.02,121.93,128.31,140.26,148.24.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 C 8 H 14 NO 4 S[M+NH 4 ] + :220.0637,found220.0638.
Preparation example 4:
under the protection of argon, 4-phenylcyclohexan-1-one (1.39 g,8 and THF (30 mL) are added into a standard Schlenk reaction tube, KHMDS (0.5M in toluene,17.6mL,8.8mmol) is added at one time after the reaction liquid is cooled to minus 15 ℃, 4-toluenesulfonic anhydride (2.87 g,8.8 mmol) is added at minus 15 ℃ at one time, the mixture is stirred for 0.5h at minus 15 ℃ after the addition is completed, the mixture is returned to room temperature for reaction, and saturated NaHCO is added after the completion of the TLC detection 3 The reaction was quenched, extracted with EA, the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then chromatographed on a column. Eluent: petroleum ether/ethyl acetate=15:1, giving a white solid, ethyl acetate/n-ethane recrystallisation, giving 841.6mg of white solid in 32% yield. M.p. 100.8-101.5 ℃. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):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 C 19 H 24 NO 3 S[M+NH 4 ] + :346.1471,found346.1466.
Preparation example 5:
to a standard Schlenk reaction tube under argon, 1-acetoneapthone (1.36 g,8 mmol) and THF (24 mL) were added. The reaction mixture was cooled to-20℃and 1.0M was added dropwise t BuOK (1.27 g,11.2 mmol) was added over 10min as a solution in THF (11 mL). After the addition was completed, the mixture was stirred at 0℃for 1.5 hours. Then cooled to-20℃and 4-toluenesulfonic anhydride (3.13 g,9.6 mmol) was added in one portion. Stirring at-20deg.C for 1 hr, stirring at 0deg.C for 6 hr, then recovering to room temperature, TLC detecting reaction completely, adding saturated NaHCO 3 The reaction was quenched, extracted with EA, the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then chromatographed on a column. Eluent: petroleum ether/ethyl acetate=20:1, giving 1.77g of yellow liquid in 54% yield. 1 H NMR(400MHz,CDCl 3 ):δ2.24(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). 13 C NMR(100MHz,CDCl 3 ):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 C 19 H 20 NO 3 S[M+NH 4 ] + :342.1158,found 342.1151.
Example 1 Compound (1 a)
At the full level of N 2 Sequentially adding NiCl to a vial having a closure plug in a glove box 2 ·6H 2 O(5.9mg,0.025mmol)，dppf(16.6mg,0.03mmol)，Zn(6.5mg,0.1mmol)，Zn(CN) 2 (47.0 mg,0.4 mmol), DMAP (91.6 mg,0.75 mmol), 4-acetylphenylmethanesulfonate (107.1 mg,0.5 mmol), CH 3 CN (5 mL). After the cover is covered, the glove box is removed, the glove box is directly placed in an oil bath at 80 ℃ for heating reaction, the temperature is cooled to room temperature after 12 hours, silica gel is filtered after TLC detection, ethyl acetate is used for washing, and column chromatography is performed after concentration. Eluent: petroleum ether/ethyl acetate=5:1, the product is 67.8mg of white solid, the yield is 93%, 1 the H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ2.67(s,3H),7.80(d,J＝8.4Hz,2H),8.07(d,J＝8.4Hz,2H). 13 C NMR(100MHz,CDCl 3 ):δ26.61,116.12,117.77,128.53,132.37,139.70,196.43.
Example 2 Compound (1 b)
At the full level of N 2 Sequentially adding NiCl to a vial having a closure plug in a glove box 2 ·6H 2 O(11.9mg,0.05mmol)，dppf(33.3mg,0.06mmol)，Zn(13.1mg,0.2mmol)，Zn(CN) 2 (47.0 mg,0.4 mmol), DMAP (91.6 mg,0.75 mmol), KI (41.5 mg,0.25 mmol), 4-methoxyphenylmethanesulfonate (107.1 mg,0.5 mmol), DMF (5 mL). Covered capThe reaction was then carried out in a glove box directly in an oil bath at 80℃and was then cooled to room temperature after 12h, followed by TLC detection. Quenched with water after the reaction was completed, et 2 O extraction three times, washing the organic phase with saturated salt water, mixing the water phases, et 2 O is back extracted twice, the organic phases are combined, dried over anhydrous magnesium sulfate, filtered and concentrated, and then column chromatography is carried out. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=10:1, the product is 53.6mg of white solid, the yield is 81%, 1 the H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ3.86(s,3H),6.95(d,J＝8.8Hz,2H),7.58(d,J＝9.2Hz,2H). 13 C NMR(100MHz,CDCl 3 ):δ55.45,103.81,114.67,119.15,133.87,162.76.
Example 3 Compound (1 c)
Using the protocol of example 2, the reaction was carried out at 80℃for 12h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=40:1, product was 20.4mg as pale yellow liquid, yield 35% and nuclear magnetic yield 72%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ2.42(s,3H),7.27(d,J＝7.2Hz,2H),7.54(d,J＝7.2Hz,2H). 13 C NMR(100MHz,CDCl 3 ):δ21.77,109.28,119.11,129.79,132.00,143.65.
Example 4 Compound (1 d)
Using the protocol of example 2, the reaction was carried out at 80℃for 12h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate/dichloromethane=100:3:1, the product was 33.2mg as pale yellow liquid, yield 42% and nuclear magnetic yield 71%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ0.93(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). 13 C NMR(100MHz,CDCl 3 ):δ13.78,22.18,33.01,35.74,109.39,111.13,129.14,132.03,148.52。
Example 5 Compound (1 e)
Using the protocol of example 1, the reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=3:1, product 40.7mg as colorless liquid, yield 61%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ2.70(brs,1H),4.76(s,2H),7.47(d,J＝8.0Hz,2H),7.62(d,J＝8.0Hz,2H)
Example 6 Compound (1 f)
Using the protocol of example 2, the reaction was carried out at 80℃for 12h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate/dichloromethane=15:1:1, product was 50.9mg as pale yellow solid, yield 69%. 1 The H NMR purity was more than 98%. m.p=70.1-71.2 ℃. 1 H NMR(400MHz,CDCl 3 ,Me 4 Si):δ2.41(s,3H),3.91(s,3H),6.78(s,1H),6.81(d,J＝8.0Hz,1H),7.41(d,J＝7.6Hz,1H). 13 C NMR(100MHz,CDCl 3 ,Me 4 Si):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 C 9 H 10 NO[M+H] + :148.0757,found 148.0752.
Example 7 Compound (1 g)
Using the protocol of example 1, the reaction was carried out at 80℃for 6h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=12:1, product 62.8mg as colorless liquid, yield85％。 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ6.07(s,2H),6.87(d,J＝8.0Hz,1H),7.03(s,1H),7.21(d,J＝8.0Hz,1H). 13 C NMR(100MHz,CDCl 3 ):δ102.13,104.77,109.00,111.24,118.74,128.07,147.91,151.42.
Example 8 Compound (1 h)
Using the protocol of example 1, the reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=12:1, product was 56.2mg as colorless liquid, yield 77%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ2.96(s,3H),6.86–6.88(m,2H),6.93(d,J＝7.2Hz,1H),7.26(dd,J＝7.6Hz,1H). 13 C NMR(100MHz,CDCl 3 ):δ40.00,112.60,114.62,116.11,119.23,119.69,129.61,150.11.
Example 9 Compound (1 i)
Using the protocol of example 1, the reaction was carried out at 80℃for 5h. Column chromatography, eluting agent: petroleum ether/ethyl acetate=10:1, product as white solid 74.5mg, yield 91%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ,Me 4 Si):δ3.81(s,6H),6.65(s,1H),6.75(s,2H). 13 C NMR(100MHz,CDCl 3 ,Me 4 Si):δ55.52,105.44,109.74,113.23,118.62,160.85.
Example 10 Compound (1 j)
The protocol of example 1 was used, but the ligand was replaced by PMePH 2 ，NiCl 2 ·6H 2 O(5.9mg,0.025mmol),PMePh 2 (12.0mg,0.06mmol),Zinc(6.5mg,0.1mmol),Zn(CN) 2 (47.0 mg,0.4 mmol), DMAP (91.6 mg,0.75 mmol), 4-benzoylphenyl methanesulfonate (138.2 mg,0.5 mmol) and CH 3 CN (5 mL) was added and reacted at 80℃for 12 hours. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=10:1, product as white solid 91.5mg, yield 88%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ7.52(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). 13 C NMR(100MHz,CDCl 3 ):δ115.49,117.89,128.51,129.93,130.10,132.05,133.20,136.18,141.08,194.90.
Example 11 Compound (1 k)
Using the protocol of example 1, the reaction was carried out at 80℃for 9h. Silica gel plate chromatography, eluting agent: petroleum ether/dichloromethane=3:2 to 1:1, product was 52.8mg as white solid, yield 82%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ7.81(s,4H). 13 C NMR(100MHz,CDCl 3 ):δ116.66,116.97,132.76.
Example 12 Compound (1 l)
Using the protocol of example 1, the reaction was carried out at 80℃for 3h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=10:1, product 73.9mg as white solid, yield 92%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ3.97(s,3H),7.76(d,J＝8.4Hz,2H),8.15(d,J＝8.4Hz,2H). 13 C NMR(100MHz,CDCl 3 ):δ52.58,116.21,117.82,129.94,132.09,133.75,165.26.
Example 13 Compound (1 m)
Using the protocol of example 1, the reaction was carried out at 80℃for 7h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=12:1, product 77.4mg as white solid, yield 88%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):δ14.09,61.64,112.72,117.79,129.28,131.60,133.06,133.48,135.72,164.43.
Example 14 Compound (1 n)
Using the protocol of example 1, the reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=3:1, product was 35.6mg as white solid, yield 68%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ7.46-7.49(m,1H),8.00(d,J＝8.0Hz,1H),8.84(d,J＝4.0Hz,1H),8.91(s,1H). 13 C NMR(100MHz,CDCl 3 ):δ110.02,116.39,123.55,139.17,152.35,152.89.
Example 15 Compound (1 o)
Using the protocol of example 2, the reaction was carried out at 80℃for 12h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=2:1, product as white solid 34.3mg, yield 44%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):δ112.98,117.19,122.72,125.80,128.05,132.86,135.47,136.45,147.38,152.43.
Example 16 Compound (1 p)
Using the protocol of example 1, the reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=7:1 to 5:1, product 57.9mg as white solid, yield 41%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ,Me 4 Si):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). 13 C NMR(100MHz,CDCl 3 ,Me 4 Si):δ13.65,21.41,25.28,25.82,28.83,31.31,35.65,37.42,44.40,47.67,50.29,109.41,119.04,126.09,129.17,132.38,137.79,145.25,220.19.
Example 17 Compound (1 q)
Using the protocol of example 1, the reaction was carried out at 50℃for 8h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=35:1, product 71.6mg as white solid, yield 93%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ7.54-7.64(m,3H),7.82-7.87(m,3H),8.15(s,1H). 13 C NMR(100MHz,CDCl 3 ):δ109.12,119.11,126.11,127.49,127.88,128.22,128.89,129.01,132.01,133.94,134.42.
Example 18 Compound (1 r)
Using the protocol of example 1, the reaction was carried out at 50℃for 6h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=35:1, product 70.9mg as pale yellow liquid, yield 93%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ,Me 4 Si):δ7.48(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). 13 C NMR(100MHz,CDCl 3 ,Me 4 Si):δ109.93,117.70,124.76,124.91,127.39,128.43,128.52,132.13,132.46,132.72,133.14.
Example 19 Compound (1 s)
Using the protocol of example 1, the reaction was carried out at 80℃for 9h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=30:1, product as white solid 66.3mg, yield 74%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):δ110.78,118.87,127.13,127.63,128.58,129.03,132.50,139.04,145.54.
Example 20 Compound (1 t)
Using the protocol of example 1, the reaction was carried out at 80℃for 12h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate/dichloromethane=100:3:1, product 71.3mg as white solid, yield 74%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ2.40(s,3H),7.27(d,J＝8.8Hz,2H),7.47(d,J＝7.2Hz,2H),7.62-7.68(m,4H). 13 C NMR(100MHz,CDCl 3 ):δ21.06,110.38,118.93,126.92,127.30,129.73,132.42,136.09,138.63,145.43.
Example 21 Compound (1 u)
Using the protocol of example 1, the reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=30:1, the product is a white solid86.7mg, yield 83%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):δ55.22,110.84,112.94,113.73,118.78,119.49,127.60,130.02,132.39,140.43,145.32,159.99.
Example 22 Compound (1 v)
Using the protocol of example 1, the reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=30:1, product as white solid 78.9mg, yield 80%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):δ110.81,115.98( 2 J C-F ＝21.5Hz),118.71,127.43,128.84( 3 J C-F ＝8.2Hz),132.51,135.15( 4 J C-F ＝3.7Hz),144.44,163.05( 1 J C-F ＝246.9Hz). 19 F NMR(376.1MHz,CDCl 3 )δ-113.13.
Example 23 Compound (1 w)
Using the protocol of example 1, the reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/dichloromethane/ethyl acetate=10:1.5:1, product was 90.6mg as white solid in 89% yield. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ7.71(d,J＝7.6Hz,4H),7.79(d,J＝7.6Hz,4H). 13 C NMR(100MHz,CDCl 3 ):δ112.33,118.36,127.89,132.82,143.49.
Example 24 Compound (1 x)
Using the protocol of example 1, the reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=30:1, product 78.4mg as white solid, yield 85%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):δ7.40(d,J＝13.2Hz,2H),7.55(s,1H),7.65(m,4H). 13 C NMR(100MHz,CDCl 3 ):δ110.29,118.83,122.51,125.78,126.67,127.03,132.54,139.82,140.16.
Example 25 Compound (2 a)
Using the protocol of example 1, the reaction was carried out at 80℃for 12h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=20:1, product as white solid 50.3mg, yield 65%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):δ23.63,25.96,114.29,117.04,124.64,127.12,127.87,128.59,129.04,134.09,143.81.
Example 26 Compound (2 b)
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Using the protocol of example 1, the reaction was carried out at 80℃for 8h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=20:1, product as white solid 70.5mg, yield 91%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):δ24.52,26.52,109.47,119.54,126.99,127.86,130.14,131.01,135.26,141.54.
Example 27 Compound (2 c)
Using the protocol of example 1, the reaction was carried out at 80℃for 7h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=15:1, product as white solid 78.9mg, yield 86%. 1 The H NMR purity was more than 98%. M.p. 59.3-61.2 ℃. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):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 C 13 H 13 N[M] + :calcd 183.1048,found 183.1042.
Example 28 Compound (2 d)
Using the protocol of example 1, the reaction was carried out at 80℃for 7h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=30:1, product as white solid 68.0mg, yield 76%. 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):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 C 13 H 10 N[M+H] + :180.0808,found 180.0808.
Example 29 Compound (2 e)
Using the protocol of example 1, the reaction was carried out at 80℃for 7h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=20:1, product as white solid 99.2mg, yield 90% (Z: e=3.2:1). 1 The H NMR purity was more than 98%. 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(100MHz,CDCl 3 ):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.
Example 30 Compound (1 a)
Using the protocol of example 1, the substrate was changed to 4-acetylphenyl 4-methylprenzenesulfonate (145.2 mg,0.5 mmol). The reaction was carried out at 80℃for 12h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=5:1, product was 69.0mg as white solid in 95% yield. 1 The H NMR purity was more than 98%.
Example 31 Compound (1 a)
Using the protocol of example 1, the substrate was changed to 4-acetylphenyl trifluoromethanesulfonate (134.1 mg,0.5 mmol). The reaction was carried out at 80℃for 12h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=5:1, product 67.2mg as white solid, yield 93%. 1 The H NMR purity was more than 98%.
Example 32 Compound (1 a)
Using the protocol of example 2, the substrate was changed to 4-acetylphenyl dimethylsulfamate (121.6 mg,0.5 mm)And (3) an ol). The reaction was carried out at 100℃for 9 hours. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=6:1, product 45.5mg as white solid, yield 63%. 1 The H NMR purity was more than 98%.
Example 32 Compound (1 b)
Using the protocol of example 2, the substrate was changed to 4-methoxyphenyl sulfurofluoridate (103.1 mg,0.5 mmol) (121.6 mg,0.5 mmol). The reaction was carried out at 80℃for 12h. Silica gel plate chromatography, eluting agent: petroleum ether/ethyl acetate=12:1, product was 51.1mg as white solid in 77% yield. 1 The H NMR purity was more than 98%.
Example 33 Compound (1 k)
At the full level of N 2 Sequentially adding NiCl to a vial having a closure plug in a glove box 2 ·6H 2 O(11.9mg,0.05mmol),dppf(33.3mg,0.06mmol),Zinc(13.1mg,0.2mmol),Zn(CN) 2 (93.9 mg,0.8 mmol), DMAP (183.3 mg,1.50 mmol), 4-chlorophenyl sulfurofluoridate (105.3 mg,0.5 mmol) and CH 3 CN (5 mL). After the cover is covered, the glove box is removed, the glove box is directly placed in an oil bath at 80 ℃ for heating reaction, the temperature is cooled to room temperature after 12 hours, silica gel is filtered after TLC detection, ethyl acetate is used for washing, and column chromatography is performed after concentration. Silica gel plate chromatography, eluting agent: petroleum ether/dichloromethane=3:2 to 1:1, product as white solid 58.7mg, 92% yield. 1 The H NMR purity was more than 98%.
Example 34 Compound (1 a)
At the full level of N 2 Sequentially adding NiCl to a vial having a closure plug in a glove box 2 ·6H 2 O(5.9mg,0.025mmol)，dppf(16.6mg,0.03mmol)，Zn(6.5mg,0.1mmol)，Zn(CN) 2 (47.0 mg,0.4 mmol), DMAP (61.1 mg,0.5 mmol), 4-acetylphenylmethanesulfonate (107.1 mg,0.5 mmol), CH 3 CN (5 mL). After the cover is covered, the glove box is removed, the glove box is directly placed in an oil bath at 80 ℃ for heating reaction, the temperature is cooled to room temperature after 12 hours, silica gel is filtered after TLC detection, ethyl acetate is used for washing, and column chromatography is performed after concentration. Eluent: petroleum ether/ethyl acetate=5:1, the product is 64.0mg of white solid, the yield is 88%, 1 the H NMR purity was more than 98%.
Example 35 Compound (1 a)
Using the protocol of example 34, the ligand was changed to dppb (12.8 mg,0.03 mmol). The reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=5:1, the product is 64.8mg of white solid, the yield is 89%, 1 the H NMR purity was more than 98%.
Example 36 Compound (1 a)
Using the protocol of example 34, the ligand was changed to Xantphos (17.4 mg,0.03 mmol). The reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=5:1. The product was 16.4mg of a white solid in 23% yield. 1 The H NMR purity was more than 98%.
Example 37 Compound (1 a)
Using the protocol of example 34, the ligand was changed to DPEphos (16.2 mg,0.03 mmol). The reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=5:1. The product was 43.3mg as a white solid in 60% yield. 1 H NMR purity of more than 98%
Example 38 Compound (1 a)
Using the protocol of example 34, ligand modification to PMe 2 Ph (8.3 mg,0.06 mmol). The reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=5:1. The product was 52.9mg of white solid in 73% yield. 1 The H NMR purity was more than 98%.
Example 39 Compound (1 a)
Using the protocol of example 34, ligand modification to PMePh 2 (12.0 mg,0.06 mmol). The reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=5:1. The product was 52.9mg of white solid in 73% yield. 1 The H NMR purity was more than 98%.
Example 40 Compound (1 a)
Using the protocol of example 34, ligand modification to PPh 3 (12.0 mg,0.06 mmol). The reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=5:1. The product was 13.2mg of a white solid in 18% yield. 1 The H NMR purity was more than 98%.
Example 41 Compound (1 a)
Using the protocol of example 34, the catalyst was modified to NiBr 2 DME (7.7 mg,0.06 mmol). The reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=5:1. The product was 63.1mg of a white solid in 87% yield. 1 The H NMR purity was more than 98%.
Example 42 Compound (1 a)
Using the protocol of example 34, the catalyst was modified to NiI 2 (7.8 mg,0.06 mmol). The reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=5:1. The product was 59.7mg of a white solid in 82% yield. 1 H NMR purity of more than 98%
Example 43 Compound (1 a)
Using the protocol of example 34, the solvent was changed to DMA (5 mL). The reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=5:1. The product was 62.5mg of a white solid in 87% yield. 1 H NMR purity of more than 98%
Example 44 Compound (1 a)
Using the protocol of example 34, the solvent was changed to NMP (5 mL). The reaction was carried out at 80℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=5:1. The product was 42.4mg of white solid in 58% yield. 1 The H NMR purity was more than 98%.
Example 45 Compound (1 a)
Using the protocol of example 34, the temperature was changed to 60 ℃. The reaction was carried out at 60℃for 12h. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=5:1. The product was 61.9mg as a white solid in 85% yield. 1 The H NMR purity was more than 98%.
Example 46 Compound (1 b)
At the full level of N 2 Sequentially adding NiCl to a vial having a closure plug in a glove box 2 ·6H 2 O(11.9mg,0.05mmol)，dppf(33.3mg,0.06mmol)，Zn(13.1mg,0.2mmol)，Zn(CN) 2 (47.0 mg,0.4 mmol), DMAP (91.6 mg,0.75 mmol), naI (37.5 mg,0.25 mmol), 4-methoxyphenylmethanesulfonate (107.1 mg,0.5 mmol), DMF (5 mL). After the cover is covered, the glove box is removed, the glove box is directly placed in an oil bath at 80 ℃ for heating reaction, the glove box is cooled to room temperature after 12 hours, and the reaction is detected by TLC. Quenched with water after the reaction was completed, et 2 O extraction three times, washing the organic phase with saturated salt water, mixing the water phases, et 2 O is back extracted twice, the organic phases are combined, dried over anhydrous magnesium sulfate, filtered and concentrated, and then column chromatography is carried out. Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=10:1, the product is white solid 43.2mg, the yield is 65%, 1 the H NMR purity was more than 98%.
Example 47 Compound (1 b)
Using the protocol of example 46, the additive was changed to Et 4 NI (64.3 mg,0.25 mmol). Silica gel column chromatography, eluting agent: petroleum ether/ethyl acetate=10:1, product 45.9mg as white solid, yield 70%. 1 The H NMR purity was more than 98%.
Claims (27)
1. The preparation method of the aromatic nitrile compound shown in the formula I comprises the following steps: under the protection of inert gas, in the presence of nickel complex, metallic zinc and additive, carrying out cross coupling reaction as shown below on aryl or heteroaryl sulfonate compound as shown in formula II and cyanation reagent; wherein the additive is 4-dimethylaminopyridine, and the cyanation reagent is zinc cyanide;
in the aromatic nitrile compound shown in the formula I and the aryl or heteroaryl sulfonate compound shown in the formula II,
n is 0, 1 or 2;
R 1 identical or different, each independently selected from C 1 -C 6 Linear or branched alkoxy, -NR b R c 、R g Substituted C 3 -C 10 Or R is aryl or heteroaryl h Substituted C 1 -C 6 Straight or branched alkyl of (a); wherein R is b And R is c Each independently is-H or C 1 -C 4 Straight or branched alkyl of (a); r is R g And R is h Each independently selected from-H, -OH, C 1 -C 4 Straight-chain or branched alkoxy and C 1 -C 4 One or more of a linear or branched alkyl group;
alternatively, any two adjacently substituted R 1 Together with the atoms of the ring alpha to which they are each attached, form a carbocycle or carbocycle which is fused to the ring alpha, said carbocycle or carbocycle being a 3-5 membered ring, said carbocycle containing 1 or 2 heteroatoms selected from O, N and S;
-OS(＝O) 2 R is trifluoromethanesulfonyl, methanesulfonyl or p-toluenesulfonyl;
the ring alpha is benzene ring, naphthalene ring, pyridine ring or quinoline ring.
2. The method of claim 1, wherein,
when R is g And R is h Any one of which is C 1 -C 4 When straight or branched alkoxy, said C 1 -C 4 Is C 1 -C 3 Straight or branched alkoxy of (a);
and/or when R b 、R c 、R g And R is h Any one of which is C 1 -C 4 In the case of a linear or branched alkyl group, said C 1 -C 4 Is C 1 -C 3 Straight or branched alkyl of (a).
3. The method of claim 1, wherein,
when R is g And R is h Any one of which is C 1 -C 4 When straight or branched alkoxy, said C 1 -C 4 Is methoxy, ethoxy, propoxy or isopropoxy;
and/or when R b 、R c 、R g And R is h Any one of which is C 1 -C 4 In the case of a linear or branched alkyl group, said C 1 -C 4 The straight or branched alkyl of (a) is methyl, ethyl, propyl or isopropyl.
4. The method of claim 1, wherein,
when R is 1 Is C 1 -C 6 When straight or branched alkoxy, said C 1 -C 6 Is C 1 -C 3 Straight or branched alkoxy of (a);
and/or when R 1 is-NR b R c When R is b And R is c Each independently is C 1 -C 4 Straight or branched alkyl of (a);
and/or when R 1 Is R g Substituted C 3 -C 10 In the case of aryl or heteroaryl groups of (C) 3 -C 10 Is phenyl or thienyl;
and/or when R 1 Is R h Substituted C 1 -C 6 In the case of a linear or branched alkyl group, said C 1 -C 6 Is C 1 -C 3 Straight or branched alkyl of (a).
5. The method according to claim 4, wherein,
when R is 1 Is C 1 -C 6 When straight or branched alkoxy, said C 1 -C 6 Is methoxy, ethoxy, propoxy or isopropoxy;
and/or when R 1 is-NR b R c When R is b And R is c Each independently is methyl, ethyl, propyl or isopropyl;
and/or when R 1 Is R h Substituted C 1 -C 6 In the case of a linear or branched alkyl group, said C 1 -C 6 The straight or branched alkyl of (a) is methyl, ethyl, propyl or isopropyl.
6. The method of claim 1, wherein,
when n is 1, R 1 Methyl, n-butyl, methoxy or amino;
and/or, when n is 2, R 1 Identical or different, each independently selected from methyl or methoxy; or two R 1 Together with the atoms of the ring alpha to which they are each attached form a dioxolyl group.
7. The preparation method of claim 1, wherein the aryl or heteroaryl sulfonate compound of formula II and the aromatic nitrile compound of formula I are any one of the following pairs of compounds:
8. the preparation method of the aromatic nitrile compound as shown in the formula I in the claim 1,
the inert gas is one or more of nitrogen, helium, argon and neon;
and/or the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to DMAP is 1:0.1-1:10;
and/or the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the metal zinc is 1:0.01-1:10;
and/or the nickel complex is NiBr 2 (PPh 3 ) 2 And/or NiCl 2 (dppf)；
And/or the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the nickel complex is 1:0.01-1:1;
and/or the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the cyanation reagent is 1:0.1-1:10;
and/or the solvent is one or more of an aromatic hydrocarbon solvent, an ether solvent, a halogenated hydrocarbon solvent, a nitrile solvent, an amide solvent and a sulfoxide solvent;
And/or the molar volume ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the solvent is 0.01mmol/mL-1mmol/mL;
and/or, the reaction temperature of the cross-coupling reaction is-100-500 ℃;
and/or the reaction time of the cross-coupling reaction is 0.1-200h.
9. The preparation method of the aromatic nitrile compound as defined in claim 8, wherein in the preparation method of the aromatic nitrile compound as defined in formula I,
the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to DMAP is 1:1-1:1.5;
and/or the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the metal zinc is 1:0.1-1:1;
and/or the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the nickel complex is 1:0.02-1:0.50;
and/or the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the cyanation reagent is 1:0.5-1:2;
and/or the aromatic solvent is selected from one or more of benzene, toluene and xylene;
and/or the ether solvent is selected from one or more of diethyl ether, 1, 4-dioxane and tetrahydrofuran;
And/or the halogenated hydrocarbon solvent is selected from one or more of dichloromethane, dichloroethane and chloroform;
and/or the nitrile solvent is acetonitrile;
and/or the amide solvent is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoramide;
and/or the sulfoxide solvent is dimethyl sulfoxide;
and/or the molar volume ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the solvent is 0.1mmol/mL-0.5mmol/mL;
and/or, the reaction temperature of the cross-coupling reaction is 0-150 ℃;
and/or the reaction time of the cross-coupling reaction is 3-12h.
10. The preparation method of the aromatic nitrile compound as defined in claim 8, wherein in the preparation method of the aromatic nitrile compound as defined in formula I,
the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the metal zinc is 1:0.2-1:0.4;
and/or the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the nickel complex is 1:0.05-1:0.10;
and/or the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the cyanation reagent is 1:0.6-1:1.2;
And/or the solvent is selected from one or more of acetonitrile, N-dimethylformamide and N, N-dimethylacetamide;
and/or, the reaction temperature of the cross-coupling reaction is 50-100 ℃.
11. The preparation method of the aromatic nitrile compound as defined in claim 8, wherein in the preparation method of the aromatic nitrile compound as defined in formula I,
the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the cyanation reagent is 1:0.8;
and/or the reaction temperature of the cross-coupling reaction is 60-80 ℃.
12. The preparation method of the aromatic nitrile compound as shown in the formula I in the claim 1,
the reaction system is provided with other additives besides the additive DMAP, wherein the other additives are quaternary ammonium salts and/or inorganic salts;
and/or the nickel complex is subjected to in-situ coordination in a reaction system by a nickel precursor catalyst and an applicable ligand and then participates in the reaction; wherein the nickel precursor catalyst is selected from Ni (cod) 2 、NiCl 2 、NiBr 2 、NiI 2 、NiBr 2 (diglyme)、NiCl 2 (glyme)、NiBr 2 (DME)、NiF 2 And NiCl 2 ·6H 2 One or more of O; suitable ligands for the nickel precursor catalyst are selected from one or more of triphenylphosphine, triethylphosphine, tributylphosphine, tricyclohexylphosphine, bis-diphenylphosphine methane, dimethylphenylphosphine, diphenylmethylphosphine, 1, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1, 4-bis (diphenylphosphine) butane, 1' -bis (diphenylphosphine) ferrocene, 9-dimethyl-4, 5-bis-diphenylphosphine xanthene, 4, 5-bis (di-t-butylphosphine) -9, 9-dimethylxanthene and 3- (dicyclohexylphosphino) -1-methyl-2-phenyl-1H-indole.
13. The preparation method of the aromatic nitrile compound as defined in claim 12, wherein in the preparation method of the aromatic nitrile compound as defined in formula I,
the quaternary ammonium salt is tetraethylammonium iodide;
and/or the inorganic salt is selected from one or more of sodium iodide, potassium iodide and lithium iodide;
and/or when the reaction system further comprises quaternary ammonium salt and/or inorganic salt, the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the quaternary ammonium salt and/or inorganic salt is 1:0.1-1:10;
and/or the nickel precursor catalyst is selected from NiBr 2 (DME)、NiI 2 And NiCl 2 ·6H 2 One or more of O;
and/or the suitable ligand of the nickel precursor catalyst is selected from one or more of bis-diphenylphosphine methane, diphenylmethyl phosphine, 1, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1, 4-bis (diphenylphosphine) butane, 1' -bis (diphenylphosphine) ferrocene and 9, 9-dimethyl-4, 5-bis-diphenylphosphine xanthene;
and/or the molar ratio of the nickel precursor catalyst to the applicable ligand is 1:1-1:10.
14. The preparation method of the aromatic nitrile compound as defined in claim 12, wherein in the preparation method of the aromatic nitrile compound as defined in formula I,
The quaternary ammonium salt is potassium iodide;
and/or when the reaction system further comprises quaternary ammonium salt and/or inorganic salt, the molar ratio of the aryl or heteroaryl sulfonate compound shown in the formula II to the quaternary ammonium salt and/or inorganic salt is 1:0.5-1:1;
and/or, suitable ligands for the nickel precursor catalyst are selected from one or more of diphenylmethylphosphine, 1' -bis (diphenylphosphino) ferrocene, and 9, 9-dimethyl-4, 5-bis-diphenylphosphino xanthene;
and/or the molar ratio of the nickel precursor catalyst to the applicable ligand is 1:1-1:5.
15. The preparation method of the aromatic nitrile compound as defined in claim 14, wherein in the preparation method of the aromatic nitrile compound as defined in formula I,
the molar ratio of the nickel precursor catalyst to the suitable ligand is 1:1.2.
16. A method for preparing an alkenyl nitrile compound shown in a formula III, which comprises the following steps: under the protection of inert gas, in the presence of nickel complex, metallic zinc and additive, carrying out cross coupling reaction as shown in IV on alkenyl sulfonate compound and cyanation reagent; wherein the additive is 4-dimethylaminopyridine; the cyanation reagent is zinc cyanide;
In the alkenyl nitrile compound shown in the formula III and the alkenyl sulfonate compound shown in the formula IV,
R 2 、R 3 and R is 4 Each independently selected from-H or- (CH) 2 )x-R m Substituted C 3 -C 10 Aryl or heteroaryl of (a); wherein R is m is-H; x is 1;
-OS(＝O) 2 r is p-toluenesulfonyl.
17. The method of claim 16, wherein,
the- (CH) 2 )x-R m Substituted C 3 -C 10 The C is aryl or heteroaryl 3 -C 10 Is C 6 -C 10 Aryl groups of (a).
18. The method of claim 17, wherein said- (CH) 2 )x-R m Substituted C 3 -C 10 The C is aryl or heteroaryl 3 -C 10 Is phenyl or naphthyl.
19. The method according to claim 16, wherein the alkenyl sulfonate compound represented by formula IV and the alkenyl nitrile compound represented by formula III are any one of the following pairs of compounds:
20. the process according to claim 16, wherein in the process for producing an alkenylnitrile compound of the formula III,
the inert gas is one or more of nitrogen, helium, argon and neon;
and/or the mol ratio of the alkenyl sulfonate compound shown in the formula IV to DMAP is 1:0.1-1:10;
And/or the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the metal zinc is 1:0.01-1:10;
and/or the nickel complex is NiBr 2 (PPh 3 ) 2 And/or NiCl 2 (dppf)；
And/or the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the nickel complex is 1:0.01-1:1;
and/or the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the cyanation reagent is 1:0.1-1:10;
and/or the solvent is one or more of an aromatic hydrocarbon solvent, an ether solvent, a halogenated hydrocarbon solvent, a nitrile solvent, an amide solvent and a sulfoxide solvent; and/or the molar volume ratio of the alkenyl sulfonate compound shown in the formula IV to the solvent is 0.01mmol/mL-1mmol/mL;
and/or, the reaction temperature of the cross-coupling reaction is-100-500 ℃;
and/or the reaction time of the cross-coupling reaction is 0.1-200h.
21. The process according to claim 20, wherein in the process for producing an alkenylnitrile compound of the formula III,
the mol ratio of the alkenyl sulfonate compound shown in the formula IV to DMAP is 1:1-1:1.5;
And/or the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the metal zinc is 1:0.1-1:1;
and/or the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the nickel complex is 1:0.02-1:0.50;
and/or the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the cyanation reagent is 1:0.5-1:2;
and/or the aromatic solvent is one or more of benzene, toluene and xylene;
and/or the ether solvent is selected from one or more of diethyl ether, 1, 4-dioxane and tetrahydrofuran;
and/or the halogenated hydrocarbon solvent is selected from one or more of dichloromethane, dichloroethane and chloroform;
and/or the nitrile solvent is acetonitrile;
and/or the amide solvent is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide and hexamethylphosphoramide;
and/or the sulfoxide solvent is dimethyl sulfoxide;
and/or the molar volume ratio of the alkenyl sulfonate compound shown in the formula IV to the solvent is 0.1mmol/mL-0.5mmol/mL;
and/or, the reaction temperature of the cross-coupling reaction is 0-150 ℃;
And/or the reaction time of the cross-coupling reaction is 3-12h.
22. The process according to claim 20, wherein in the process for producing an alkenylnitrile compound of the formula III,
the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the metal zinc is 1:0.2-1:0.4;
and/or the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the nickel complex is 1:0.05-1:0.10;
and/or the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the cyanation reagent is 1:0.6-1:1.2;
and/or the solvent is selected from one or more of acetonitrile, N-dimethylformamide and N, N-dimethylacetamide;
and/or, the reaction temperature of the cross-coupling reaction is 50-100 ℃.
23. The process according to claim 20, wherein in the process for producing an alkenylnitrile compound of the formula III,
the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the cyanation reagent is 1:0.8;
and/or the reaction temperature of the cross-coupling reaction is 60-80 ℃.
24. The process according to claim 16, wherein in the process for producing an alkenylnitrile compound of the formula III,
the reaction system is provided with other additives besides the additive DMAP, wherein the other additives are quaternary ammonium salts and/or inorganic salts;
and/or the nickel complex is subjected to in-situ coordination in a reaction system by a nickel precursor catalyst and an applicable ligand and then participates in the reaction; wherein the nickel precursor catalyst is selected from Ni (cod) 2 、NiCl 2 、NiBr 2 、NiI 2 、NiBr 2 (diglyme)、NiCl 2 (glyme)、NiBr 2 (DME)、NiF 2 And NiCl 2 ·6H 2 One or more of OThe method comprises the steps of carrying out a first treatment on the surface of the Suitable ligands for the nickel precursor catalyst are selected from one or more of triphenylphosphine, triethylphosphine, tributylphosphine, tricyclohexylphosphine, bis-diphenylphosphine methane, dimethylphenylphosphine, diphenylmethylphosphine, 1, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1, 4-bis (diphenylphosphine) butane, 1' -bis (diphenylphosphine) ferrocene, 9-dimethyl-4, 5-bis-diphenylphosphine xanthene, 4, 5-bis (di-t-butylphosphine) -9, 9-dimethylxanthene and 3- (dicyclohexylphosphino) -1-methyl-2-phenyl-1H-indole.
25. The process according to claim 24, wherein in the process for producing an alkenylnitrile compound of the formula III,
The quaternary ammonium salt is tetraethylammonium iodide;
and/or the inorganic salt is selected from one or more of sodium iodide, potassium iodide and lithium iodide;
and/or when the reaction system further comprises quaternary ammonium salt and/or inorganic salt, the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the quaternary ammonium salt and/or inorganic salt is 1:0.1-1:10;
and/or the nickel precursor catalyst is selected from NiBr 2 (DME)、NiI 2 And NiCl 2 ·6H 2 One or more of O;
and/or the suitable ligand of the nickel precursor catalyst is selected from one or more of bis-diphenylphosphine methane, diphenylmethyl phosphine, 1, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1, 4-bis (diphenylphosphine) butane, 1' -bis (diphenylphosphine) ferrocene and 9, 9-dimethyl-4, 5-bis-diphenylphosphine xanthene;
and/or the molar ratio of the nickel precursor catalyst to the ligand is 1:1-1:10.
26. The process according to claim 24, wherein in the process for producing an alkenylnitrile compound of the formula III,
the inorganic salt is potassium iodide;
and/or when the reaction system further comprises quaternary ammonium salt and/or inorganic salt, the molar ratio of the alkenyl sulfonate compound shown in the formula IV to the quaternary ammonium salt and/or inorganic salt is 1:0.5-1:1;
And/or, suitable ligands for the nickel precursor catalyst are selected from one or more of diphenylmethylphosphine, 1' -bis (diphenylphosphino) ferrocene, and 9, 9-dimethyl-4, 5-bis-diphenylphosphino xanthene;
and/or the molar ratio of the nickel precursor catalyst to the ligand is 1:1-1:5.
27. The method of claim 26, wherein the molar ratio of the nickel precursor catalyst to the ligand in the method of preparing the alkenylnitrile compound of formula III is 1:1.2.
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