CN111484472A - Process for producing alkyl nitrile compound - Google Patents
Process for producing alkyl nitrile compound Download PDFInfo
- Publication number
- CN111484472A CN111484472A CN201910081372.4A CN201910081372A CN111484472A CN 111484472 A CN111484472 A CN 111484472A CN 201910081372 A CN201910081372 A CN 201910081372A CN 111484472 A CN111484472 A CN 111484472A
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- China
- Prior art keywords
- unsubstituted
- substituted
- group
- compound
- aryl
- Prior art date
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- -1 alkyl nitrile compound Chemical class 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims description 33
- 230000008569 process Effects 0.000 title description 4
- 150000001336 alkenes Chemical class 0.000 claims abstract description 57
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 40
- 229910001868 water Inorganic materials 0.000 claims abstract description 39
- 239000003054 catalyst Substances 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- 238000007333 cyanation reaction Methods 0.000 claims abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 238000006722 reduction reaction Methods 0.000 claims abstract description 11
- 229940125904 compound 1 Drugs 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 7
- 230000001681 protective effect Effects 0.000 claims abstract description 7
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 121
- 150000001875 compounds Chemical class 0.000 claims description 87
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 78
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 77
- 239000003446 ligand Substances 0.000 claims description 56
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 39
- 125000005842 heteroatom Chemical group 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 229910052759 nickel Inorganic materials 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 30
- 150000002815 nickel Chemical class 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 25
- 150000002816 nickel compounds Chemical class 0.000 claims description 24
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 22
- 239000011701 zinc Substances 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 claims description 15
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 15
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 14
- 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 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 150000002825 nitriles Chemical class 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 239000003638 chemical reducing agent Substances 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 229910052786 argon Inorganic materials 0.000 claims description 11
- 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 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 238000006467 substitution reaction Methods 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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 239000007789 gas Substances 0.000 claims description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 229910021588 Nickel(II) iodide Inorganic materials 0.000 claims description 4
- 239000003849 aromatic solvent Substances 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical group [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 4
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 claims description 4
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 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 2
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 claims description 2
- 125000006017 1-propenyl group Chemical group 0.000 claims description 2
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 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 2
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- JCUYKJIVFPLSFL-UHFFFAOYSA-N P.C1=CC=CC=2OC3=CC=CC=C3CC12 Chemical compound P.C1=CC=CC=2OC3=CC=CC=C3CC12 JCUYKJIVFPLSFL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 2
- 239000008367 deionised water Substances 0.000 claims description 2
- 229910021641 deionized water Inorganic materials 0.000 claims description 2
- XXECWTBMGGXMKP-UHFFFAOYSA-L dichloronickel;2-diphenylphosphanylethyl(diphenyl)phosphane Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 XXECWTBMGGXMKP-UHFFFAOYSA-L 0.000 claims description 2
- ZBQUMMFUJLOTQC-UHFFFAOYSA-N dichloronickel;3-diphenylphosphaniumylpropyl(diphenyl)phosphanium Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1[PH+](C=1C=CC=CC=1)CCC[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 ZBQUMMFUJLOTQC-UHFFFAOYSA-N 0.000 claims description 2
- HASCQPSFPAKVEK-UHFFFAOYSA-N dimethyl(phenyl)phosphine Chemical compound CP(C)C1=CC=CC=C1 HASCQPSFPAKVEK-UHFFFAOYSA-N 0.000 claims description 2
- ZEIZANJFJXHMNS-UHFFFAOYSA-N ditert-butyl-(5-ditert-butylphosphanyl-9,9-dimethylxanthen-4-yl)phosphane Chemical compound O1C2=C(P(C(C)(C)C)C(C)(C)C)C=CC=C2C(C)(C)C2=C1C(P(C(C)(C)C)C(C)(C)C)=CC=C2 ZEIZANJFJXHMNS-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 2
- 229910052748 manganese Inorganic materials 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 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 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- DISPOJHKKXSCLS-UHFFFAOYSA-N n-diaminophosphorylmethanamine Chemical compound CNP(N)(N)=O DISPOJHKKXSCLS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052754 neon Inorganic materials 0.000 claims description 2
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 claims description 2
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 claims description 2
- NLEUXPOVZGDKJI-UHFFFAOYSA-N nickel(2+);dicyanide Chemical compound [Ni+2].N#[C-].N#[C-] NLEUXPOVZGDKJI-UHFFFAOYSA-N 0.000 claims description 2
- QEKXARSPUFVXIX-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dibromide Chemical compound [Ni+2].[Br-].[Br-].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QEKXARSPUFVXIX-UHFFFAOYSA-L 0.000 claims description 2
- BFSQJYRFLQUZKX-UHFFFAOYSA-L nickel(ii) iodide Chemical compound I[Ni]I BFSQJYRFLQUZKX-UHFFFAOYSA-L 0.000 claims description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims 8
- 150000004677 hydrates Chemical class 0.000 claims 8
- 125000000623 heterocyclic group Chemical group 0.000 claims 6
- 150000003254 radicals Chemical class 0.000 claims 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 3
- 239000011630 iodine Substances 0.000 claims 3
- 229910052740 iodine Inorganic materials 0.000 claims 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 2
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 claims 2
- 125000001033 ether group Chemical group 0.000 claims 2
- 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 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 238000005669 hydrocyanation reaction Methods 0.000 abstract description 27
- 239000000758 substrate Substances 0.000 abstract description 10
- 125000000524 functional group Chemical group 0.000 abstract description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 250
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
- 238000006243 chemical reaction Methods 0.000 description 93
- 238000005160 1H NMR spectroscopy Methods 0.000 description 63
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 60
- 239000000047 product Substances 0.000 description 54
- 238000005481 NMR spectroscopy Methods 0.000 description 53
- 239000003208 petroleum Substances 0.000 description 46
- 238000010898 silica gel chromatography Methods 0.000 description 45
- 239000003480 eluent Substances 0.000 description 44
- 239000007788 liquid Substances 0.000 description 41
- 230000035484 reaction time Effects 0.000 description 37
- 238000000746 purification Methods 0.000 description 35
- 239000002994 raw material Substances 0.000 description 19
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 238000001914 filtration Methods 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000003921 oil Substances 0.000 description 10
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- DNBKBOHCTZPNEL-UHFFFAOYSA-N undec-1-en-1-one Chemical compound CCCCCCCCCC=C=O DNBKBOHCTZPNEL-UHFFFAOYSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- 229940126673 western medicines Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
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Abstract
The invention discloses a preparation method of alkyl nitrile compounds. Specifically, the preparation method comprises the following steps: in an organic solvent, in the presence of protective gas, under the action of a catalyst, carrying out reduction reaction on olefin shown as a formula I, a cyanation reagent and water as shown in the specification; the alkyl nitrile compound 1 is a compound II and/or a compound III. The preparation method provided by the invention is mild in condition, can realize olefin hydrocyanation more safely and efficiently, and has good substrate universality and functional group compatibility.
Description
Technical Field
The invention relates to a preparation method of alkyl nitrile compounds.
Background
Nitrile compounds are widely distributed in medicine, pesticides, functional materials and molecules with biological activity. Acetonitrile, for example, is often used as a solvent for organic reactions as the smallest molecular weight nitrile compound. Acrylonitrile is often used as a monomer for a polymer, and has an important position in polymer materials such as synthetic fibers, resins, rubbers, and the like. Halogen-containing aryl nitriles such as bromoxynil and ioxynil are commonly used as pesticides. Ricinine produced in microorganisms and plants also contains cyano functionality. Many nitriles and their derivatives are found to have very high pharmaceutical activity, such as anti-inflammatory, analgesic ibuprofen and naproxen are the corresponding derivatives of benzonitrile, and the cyano-containing western medicines vildagliptin and saxagliptin are the medicines for regulating blood sugar.
Nitrile compounds are important synthetic intermediates in organic synthesis, and can be easily converted into other useful functional compounds such as aldehydes, ketones, carboxylic acids, esters, amines, amides and the like, under the activation action of transition metals, C-CN is cleaved, and then can be used as an electrophilic reagent to carry out a coupling reaction or a carbocyanization reaction with alkyne and the like. In view of the important value of nitrile compounds, the research of developing a simple, efficient and environment-friendly cyanation reaction method to synthesize nitrile compounds is especially necessary.
Transition metal catalyzed hydrocyanation of olefins is one of the important processes for the synthesis of alkylnitriles, as described in:
(a)T.V.Rajanbabu,2011.Hydrocyanation of Alkenes and Alkynes.OrganicReactions.Volume 75,chapter 1,pp.1-74；
(b)L.Bini,C.Müller,D.Vogt,ChemCatChem 2010,2,590-608.
(c)A.L.Casalnuovo,T.V.Rajanbabu,Transition-metal catalyzed alkene andalkyne hydrocyanations.In Transition Metals for Organic Synthesis:BuildingBlocks and Fine Chemicals；M.Beller,C.Bolm,Eds.；Wiley-VCH,2008；Chapter 2.5,andreferences therein；
(d)M.Beller,J.Seayad,A.Tillack,H.Jiao,Angew.Chem.,Int.Ed.2004,43,3368-3398and references therein.
(e)C.A.Tolman,R.J.McKinney,W.C.Seidel,J.D.Druliner,W.R.Stevens,Adv.Catal.1985,33,1-46and references therein.
the reactions reported in the above documents are reactions of olefins catalyzed by transition metals such as Ni, Pd or Co with highly toxic hydrogen cyanide, which limits the development of the reaction, or substrates capable of forming hydrogen cyanide, such as acetone cyanohydrin or trimethylcyanosilane, to form cyanation products. The hydrogen-cyanation reactions for olefins, especially non-activated olefins, are relatively limited in the literature.
The current research on the hydrocyanation of olefins has focused primarily on the nickel-catalyzed study of olefins with hydrogen cyanide or acetone cyanohydrin, with the most mature development being the hydrocyanation of 1, 3-butadiene. Two hydrocyanation reactions of 1, 3-butadiene with nickel as a catalyst to synthesize adiponitrile, a nylon 66 precursor, was developed by Tolman et al in the beginning of the 20 th century, 70 s, by dupont. The annual output of the method reaches 100 million tons, and compared with a butadiene chlorination cyanidation method, the method has the advantages of reducing the cost by 15 percent, saving energy by 45 percent, along with short route, energy conservation, environmental protection, low cost and the like. The process is very mature nowadays, but monopolized by foreign companies, and the industrial production of nylon 66 in China is greatly limited. In addition, it has been reported in the literature that hydrocyanation of aryl olefins is also relatively easy to control their regioselectivity, and that the reaction is more prone to produce branched nitriles such as formula II due to the stabilizing effect of the aryl group. In recent years, scientists have developed novel ligands to control the regioselectivity and enantioselectivity of olefin hydrocyanation reactions, with some favorable results. As described in the following documents:
(f)P.W.N.M.van Leeuwen,in Homogeneous Catalysis:Understanding of theArt,Kluwer Academic Publishers,Dordrecht,The Netherlands,2004,p.229.；
among the reactions mentioned are, in particular, the isomerization of 2M3BN to 3PN under the action of nickel and the isomerization of 3PN to 4PN under the action of Lewis acid and nickel. The reaction process is as follows: butadiene is subjected to a first hydrocyanation reaction under the action of a nickel catalyst to form two cyanidation products, of which 2-methyl-3-butanenitrile (2M3BN) can be isomerized to the desired trans-3-pentenenitrile (3PN), and a Lewis acid (for example AlCl) is subsequently added3、ZnCl2、BPh3Etc.) promote the alkene isomerization reaction of trans-3-pentenenitrile (3PN) to obtain 4-pentenenitrile (4PN), and the generated end alkene nitrile generates hydrocyanation reaction of anti-Markov addition once again to obtain Adiponitrile (ADN) smoothly.
In addition to 1,3-The hydrocyanation of butadiene, aryl olefins, is also a research focus of scientists, and this reaction is of great interest, especially in asymmetric chemistry. Tolman et al first reported a nickel-catalyzed hydrocyanation of styrene. With Ni [ P (O-O-tolyl)3]3The reaction tends to follow the rule of Ma's addition in the case of catalysts this remarkable regioselectivity may be due to the interaction of the nickel intermediate with the aromatic ring or η3The benzylnickel intermediate is more stable. Adding Lewis acid BPh into the system3The linear nitrile produced by the reaction according to the reverse Markov addition rule was increased by up to 33%. They believe that the coordination of the Lewis acid to the cyano group increases the steric hindrance of the nickel center. In the latter literature, new ligands are constantly being developed and used for the hydrocyanation of olefins, chiral diphosphine ligands being developed particularly rapidly. Diphosphite type, binaphthol-derived diphosphite, Xantphos type, Xantphos and Thixantphos based hypophosphite type ligands and the like can be used in the hydrocyanation reaction of olefins. Such as those reported in the following documents:
in 2000, Chan group by Ni (cod)2As a catalyst, chiral diphosphite is used as a diphosphine ligand to catalyze the hydrocyanation reaction of acetone cyanohydrin to olefin. The authors found by comparative experiments that the conversion of the reaction increased when the reaction temperature was increased to 100 ℃, and that if the amount of ligand was increased to 7 times that of nickel, the reaction could be substantially complete and showed good regioselectivity, but the ee value of the reaction was less affected. Although the ee value is still at a moderate level, it is still over the past report. The authors believe that excess ligand favors the shift of the equilibrium towards the generation of active catalytic species.
(g)M.Yan,Q.-Y.Xu,A.S.C.Chan,Tetrahedron:Asymmetry 2000,11,845–849
The Breit group in 2008 designs a bidentate ligand obtained by self-assembling two phosphine ligands by utilizing hydrogen bonding, and the ligand is expected to be applied to a nickel-catalyzed hydrocyanation reaction, and experimental results show that the self-assembled ligand can be indeed coordinated with metallic nickel, and can successfully catalyze the hydrocyanation reaction of aryl olefin or 1, 3-butadiene compounds, which is the first report that the ligand has coordination performance with nickel (0). Surprisingly, such ligands also give branched products with high regioselectivity.
(h)M,de Greef,B,Breit,Angew.Chem.Int.Ed.2009,48,551-554.
In 2013, Schmalz's group found that the combination of MeOH and TMSCN can generate HCN in situ to participate in the reaction, and chiral phosphite L is used as a ligand, so that various olefins can be efficiently converted into chiral nitriles at room temperature.
(i)A.Falk,A.-L.
H.-G.Schmalz,Angew.Chem.Int.Ed.2013,52,1576-1580.
In all olefin hydrocyanation reactions, the difficulty of non-activated olefins participating in the reaction is greater. Taylor et al first reported that zero-valent nickel catalyzes the hydrocyanation of non-activated olefins. By screening, the authors found AlCl3When the nitrile-containing amine-containing nitrile is used as an additive, the reaction is more efficient, and the reaction can be promoted to generate more anti-Markov addition products, namely chain nitriles. As shown in the above table, steric hindrance of substitution on the other side of the olefin has a significant effect on regioselectivity of the reaction when the substituent is less sterically hinderedWhen the substituent(s) of (2) such as methyl group(s) is (are) changed to substituent(s) having a large steric hindrance such as isopropyl group and tert-butyl group, the selectivity is greatly improved and almost only chain nitrile(s) is (are) produced. 1-hexene promoted by the Lewis acid can also give heptanitrile with good regioselectivity.
(j)B.W.Taylor,H.E.Swift,J.Catal.1972,26,254-260.
Koji Nemoto et al catalyzed the hydrocyanation of olefins for the first time in 2016 by zinc reduction of stable divalent nickel to zero-valent nickel. Not only can aryl alkene smoothly undergo hydrogen-cyanidation reaction, but also the unactivated alkyl alkene can be smoothly converted into nitrile compound under the catalytic system. The reaction mainly uses liquid acetone cyanohydrin which is more stable than HCN to generate HCN and olefin in situ to generate addition reaction, but the toxicity of the acetone cyanohydrin cannot be ignored. Unfortunately, each class of aryl olefins and alkyl olefins do not have good regioselectivity under these conditions.
(k)Nemoto,K.；Nagafuchi,T.；Tominaga,K.；Sato,K.Tetrahedron Lett.2016,57,3199.
Since hydrogen cyanide is a highly toxic and volatile liquid (bp27 ℃), an explosive polymerization reaction may occur in the presence of alkali, and the method is extremely dangerous in laboratories and industrial production, so that the development of a safe and efficient hydrogen-cyanation reaction, especially a hydrogen-cyanation reaction with high regio-and stereoselectivity, is urgent and needed.
They used nickel complexes as catalysts to generate H-Ni-CN species in situ by C-CN bond cleavage of alkyl nitriles and β -H elimination reactions, which then undergo intercalation and reductive elimination reactions with olefins to yield hydrocyanation products.
(l)X.Fang,P.Yu,B.Morandi,Science,2016,351,832-836.
The reactions reported above, while making some progress in the regioselectivity and enantioselectivity of nickel-catalyzed olefin hydrocyanation reactions, still use highly toxic and volatile hydrogen cyanide and are still to be improved and broken through in terms of substrate universality, functional group compatibility, and efficiency and selectivity of non-activated alkyl olefin hydrocyanation reactions.
Therefore, a safe and efficient preparation method of nitrile compounds with wide substrate adaptability is still a method which needs to be developed urgently in the field.
Disclosure of Invention
The invention aims to solve the technical problems that a cyanation reagent hydrogen cyanide used in the existing nickel-catalyzed alkene hydrocyanation reaction is extremely toxic and volatile, the substrate universality and the functional group compatibility are poor, and the efficiency and the selectivity of the hydrocyanation reaction of non-activated alkyl alkene are poor, so that the preparation method of the alkyl nitrile compound is provided. The preparation method provided by the invention is mild in condition, can realize olefin hydrocyanation more safely and efficiently, and has good substrate universality and functional group compatibility.
The invention solves the technical problems through the following technical scheme.
The invention provides a preparation method of alkyl nitrile compound 1, which comprises the following steps: in an organic solvent, in the presence of protective gas, under the action of a catalyst, carrying out reduction reaction on olefin shown as a formula I, a cyanation reagent and water as shown in the specification; the alkyl nitrile compound 1 is a compound II and/or a compound III;
the cyanation reagent is one or more of sodium cyanide, potassium cyanide, nickel cyanide and zinc cyanide;
the catalyst comprises a nickel compound and a phosphine ligand; the nickel compound is one or more of 0-valent nickel, monovalent nickel salt and divalent nickel salt; when the nickel-based compound comprises a divalent nickel salt, the catalyst further comprises a reducing agent;
wherein R is1Is unsubstituted or R1-1Substituted C6-14Aryl, unsubstituted or R1-2The substituted' heteroatom is selected from one or more of N, O and S, 5-20-membered heteroaryl with 1-4 heteroatom (S), unsubstituted or R1-3Substituted C1-10Alkyl, unsubstituted or R1-4Substituted C2-10Alkenyl, unsubstituted or R1-5Substituted C3-8Cycloalkyl, unsubstituted or R1-6Substituted 3-to 10-membered heterocycloalkyl in which the heteroatom is one or more selected from N, O and S and the number of heteroatoms is 1 to 4,
R1-1is-OH, -NH2、-CN、CF3Halogen, C1-10Alkyl radical, C1-10Alkoxy radical, C6-14Aryl, or, unsubstituted or R1 -1-1The substituted 'heteroatom is selected from one or more of N, O, S and B, and the number of heteroatoms is 1-4';
R1-3is-OH, -CHO,
OR1-3-1、
Unsubstituted or R1-3-4Substituted C6-14Aryl (said C)6-14Aryl radicals such as C6-10Aryl, further for example phenyl or naphthyl), unsubstituted or R1-3-5Substituted C3-6Cycloalkyl (said C)3-6Cycloalkyl groups such as cyclopropyl, cyclopentyl, or cyclohexyl);
R1-2、R1-4、R1-7、R1-8、R1-9a、R1-9b、R1-9c、R1-1-1、R1-3-2、R1-3-3a、R1-3-3band R1-3-4Independently is C1-10Alkyl (e.g. C)1-4Alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl), C1-10Alkoxy (e.g. C)1-4Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy), or unsubstituted or R1-2-1Substituted C6-14Aryl radical (C)6-14Aryl radicals such as C6-10Aryl, for example phenyl); r1-2-1is-OH, -NH2、-CN、CF3Halogen, C1-4Alkyl (e.g. methyl, ethyl, propyl or isopropyl) or C1-4Alkoxy (e.g., methoxy, ethoxy, propoxy, or isopropoxy);
R1-5、R1-6and R1-3-5Independently is ═ O (i.e. two gem-hydrogens on carbon atoms are replaced by a group O), C1-4Alkyl (e.g. methyl, ethyl, propyl, isopropyl) or C1-4Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy);
R1-10independently is H, -OH, -NH2、-CN、CF3Halogen, C1-4Alkyl (e.g. methyl, ethyl, propyl, isopropyl) or C1-4Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy); m is 0,1, 2,3 or 4;
R1-3-1is an oxygen protecting group { e.g., t-butyldiphenylsilyl (TBDPS) or t-butyldimethylsilyl (TBS) }.
In the present invention, the number of said "substitution" may be one or more, for example, 1,2, 3 or 4; when there are a plurality of "substitutions", the "substitutions" may be the same or different.
The inventionIn when R is1-1In the case of halogen, the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine.
In the present invention, when R is1-2-1In the case of halogen, the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine.
In the present invention, when R is1-10In the case of halogen, the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine.
In the present invention, when R is1Is unsubstituted or R1-1Substituted C6-14When aryl, said C6-14Aryl may be C6-10Aryl, such as phenyl or naphthyl.
In the present invention, when R is1Is unsubstituted or R1-2When the 5-to 20-membered heteroaryl group is substituted, the 5-to 20-membered heteroaryl group may be a 5-to 13-membered heteroaryl group, such as a pyridyl group (further example is
) Indolyl (another example is
) Benzothienyl (again for example
) Or carbazolyl (further e.g.
)。
In the present invention, when R is1Is unsubstituted or R1-3Substituted C1-10When alkyl, said C1-10The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl (e.g., methyl, ethyl, propyl, octyl, or nonyl).
In the present invention, when R is1Is unsubstituted or R1-4Substituted C2-10When alkenyl, said C2-10Alkenyl may be C2-6Alkenyl groups (e.g., vinyl, 1-propenyl, butenyl),2-propenyl, 1-butenyl, 2-butenyl or butadiene, further for example ethenyl).
In the present invention, when R is1Is unsubstituted or R1-5Substituted C3-8When there is a cycloalkyl group, said C3-8Cycloalkyl radicals may be C3-6Cycloalkyl (e.g., cyclopropyl, cyclopentyl, or cyclohexyl).
In the present invention, when R is1Is unsubstituted or R1-6When the 3-to 10-membered heterocycloalkyl group is substituted, the 3-to 10-membered heterocycloalkyl group can be a 3-to 6-membered heterocycloalkyl group (e.g., tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and further examples thereof
)。
In the present invention, when R is1-1Is C1-10When alkyl, said C1-10The alkyl group may be C1-4Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, further e.g., methyl or isobutyl).
In the present invention, when R is1-1Is C1-10At alkoxy, said C1-10Alkoxy may be C1-4Alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy, further e.g., methoxy).
In the present invention, when R is1-1Is C6-14When aryl, said C6-14Aryl may be C6-10Aryl (e.g., phenyl).
In the present invention, when R is1-1Is unsubstituted or R1-1-1When the 3-to 10-membered heterocycloalkyl group is substituted, the 3-to 10-membered heterocycloalkyl group may be a 3-to 6-membered heterocycloalkyl group (for example
)。
In one embodiment of the invention, when R1Is unsubstituted or R1-1Substituted C6-14Aryl, unsubstituted or R1-2The substituted heteroatom is selected from N, O and SOr more, 5-20 membered heteroaryl with 1-4 hetero atoms, unsubstituted or R1-4Substituted C2-10An alkenyl group,
Except that R1Is composed of
When the other groups are as described in any of the preceding embodiments, the compound 1 is a compound II.
In one embodiment of the invention, when R1Is unsubstituted or R1-3Substituted C1-10Alkyl, unsubstituted or R1-5Substituted C3-8Cycloalkyl, unsubstituted or R1-6Substituted 3-to 10-membered heterocycloalkyl in which the heteroatom is one or more selected from N, O and S and the number of heteroatoms is 1 to 4,
Wherein R is1-3is-CHO,
Unsubstituted or R1-3-5Substituted C3-6Cycloalkyl, OTBS, or, unsubstituted or R14Substituted C6-14Aryl, other groups as in any of the previous embodiments, said compound 1 is compound III.
In one embodiment of the invention, R1Is R1-1Substituted C6-14Aryl, 5-20 membered heteroaryl having one or more unsubstituted heteroatoms selected from N, O and S and 1-4 heteroatoms, or,
Wherein the unsubstituted 5-20 membered heteroaryl is carbazolyl; r1-1Is C1-10Alkoxy or C6-14Aryl, other groups are as described in any of the preceding schemes.
In one embodiment of the invention, R1Is unsubstituted or R1-1Substituted C6-14Aryl, unsubstitutedThe 'hetero atom (S) of (a) is (are) one or more selected from N, O and S, and the number of hetero atoms is (1) to (4)' 5-to (20) -membered heteroaryl is unsubstituted or R1-3Substituted C1-10Alkyl, unsubstituted or R1-5Substituted C3-8Cycloalkyl, unsubstituted or R1-6Substituted 3-to 10-membered heterocycloalkyl having 1 to 4 hetero atoms selected from N, O and S,
Or,
Wherein the unsubstituted 5-20 membered heteroaryl is indolyl; r1-1is-NH2、C1-10Alkoxy, unsubstituted or R1-1-1The substituted 'heteroatom is selected from one or more of N, O, S and B, and the number of heteroatoms is 1-4'; r1-3is-OH, -CHO,
OR1-3-1、
R1-3-4Substituted C6-14Aryl, unsubstituted or R1-3-5Substituted C3-6A cycloalkyl group; other groups are as described in any of the preceding schemes.
In one embodiment of the invention, R1Is unsubstituted or R1-1Substituted C6-14Aryl or 5-20 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S as unsubstituted heteroatoms; wherein the unsubstituted 5-20 membered heteroaryl is carbazolyl; r1-1Independently is-OH or CF3(ii) a Other groups are as described in any of the preceding schemes.
In one embodiment of the invention, R1Is composed of
In one embodiment of the invention, R1Is unsubstituted or R1-3Substituted C1-10An alkyl group, or,
Wherein R is1-3Is composed of
Or, unsubstituted or R1-3-4Substituted phenyl; other groups are as described in any of the preceding schemes.
In one embodiment of the present invention, the olefin represented by formula I can be selected from any of the following structures:
in one embodiment of the present invention, the olefin represented by formula I may also be selected from any of the following structures:
in one embodiment of the present invention, the olefin represented by formula I may also be selected from any of the following structures:
in the present invention, the cyanating agent is preferably zinc cyanide.
In the present invention, the organic solvent may be an organic solvent conventional in such reactions in the art, preferably one or more of an aromatic solvent (e.g., one or more of benzene, toluene and xylene), an ethereal solvent { e.g., one or more of diethyl ether, 1, 4-dioxane and tetrahydrofuran (THF }, a halogenated hydrocarbon solvent { e.g., one or more of Dichloromethane (DCM), Dichloroethane (DCE) and chloroform }, a nitrile solvent (e.g., acetonitrile), an amide solvent { e.g., N-Dimethylformamide (DMF) and/or methylphosphoramide }, and a sulfoxide solvent { e.g., Dimethylsulfoxide (DMSO) }; more preferably an ether solvent and/or a nitrile solvent.
In the present invention, the protective gas may be a protective gas commonly used in this type of reaction in the art, preferably one or more of nitrogen, helium, argon and neon; more preferably nitrogen.
In the present invention, the phosphine ligand may be a phosphine ligand commonly used in this type of reaction in the art, preferably triphenylphosphine (PPh)3) Triphenyl phosphite (P (OPh)3) Tributylphosphine (PBu)3) Tricyclohexylphosphine (PCy)3) Dimethyl phenyl phosphine (PMe)2Ph), diphenylmethylphosphine (PMePh)2) Bis-diphenylphosphinomethane (dppm), 1, 2-bis (diphenylphosphino) ethane (dppe), 1, 3-bis (diphenylphosphino) propane (dppp), 1, 4-bis (diphenylphosphino) butane (dppb), 1' -bis (diphenylphosphino) ferrocene (dppf), bis (2-diphenylphosphinophenyl) ether (DPEphos), 9-dimethyl-4, 5-bis-diphenylphosphinoanthracene (xanthphos) and 4, 5-bis (di-tert-butylphosphino) -9, 9-dimethylxanthene (di-tert-butylphosphino)tBu-Xantphos); more preferably one or more of 1, 3-bis (diphenylphosphino) propane, 1' -bis (diphenylphosphino) ferrocene and 9, 9-dimethyl-4, 5-bisdiphenylphosphinoxaanthracene.
In the present invention, the 0-valent nickel may be Ni (cod)2(cod: 1, 5-cyclooctadiene).
In the present invention, the monovalent nickel salt may be NiCl.
In the present invention, the divalent nickel salt may be Ni (acac)2(acac: diacetone), NiCl2、NiCl2(DME) (DME: ethylene glycol dimethyl ether), NiBr2(DME)、NiI2And Ni (ClO)4)2Preferably NiCl2And/or Ni (ClO)4)2。
In the present invention, in the catalyst, the nickel-based compound and the phosphine ligand may be present in a form conventional in the art, for example, the nickel-based compound and the phosphine ligand are independent compounds, or some or all of the nickel-based compound and some or all of the phosphine ligand are complexes; such as one or more of a complex of 0-valent nickel with phosphine ligands, a complex of a monovalent nickel salt with phosphine ligands, and a complex of a divalent nickel salt with phosphine ligands.
In the present invention, when part or all of the nickel-based compound and part or all of the phosphine ligand are complexes, the complex of 0-valent nickel and phosphine ligand may be Ni (PPh)3)4(ii) a The complex of the monovalent nickel salt and the phosphine ligand can be NiCl (dppf); the complex of the divalent nickel salt and the ligand can be NiCl2(PPh3)4、NiCl2(dppf)、NiBr2(PPh3)2、NiCl2(PCy3)3、NiCl2(dppp) and NiCl2(dppe).
In the present invention, in the catalyst, the nickel-based compound and the phosphine ligand are preferably independent compounds.
In the present invention, the reducing agent is preferably one or more of Zn, Mn and Al, more preferably Zn.
In one embodiment of the present invention, the catalyst is preferably a divalent nickel salt, a phosphine ligand and Zn; the divalent nickel salt is NiCl2And/or Ni (ClO)4)2The phosphine ligand is 1, 1' -bis (diphenylphosphino) ferrocene and/or 9, 9-dimethyl-4, 5-bis-diphenylphosphine xanthene phosphine ligand.
In the present invention, the nickel-based compound and the water may be in a combination conventional in the art, for example, the nickel-based compound and the water are independent compounds, or a crystalline hydrate is formed by a part or all of the nickel-based compound and a part or all of the water; the crystalline hydrate is formed by water and/or the divalent nickel salt.
In the present invention, the water may be water conventionally used in the art, and is not particularly limited as long as it does not affect the reaction, for example, deionized water.
In the present invention, when part or all of the nickel compound and part or all of the water form a crystalline hydrate, the crystalline hydrate formed by the divalent nickel salt and the water may be NiCl2·6H2O、NiI2·6H2O、Ni(acac)2·2H2O and Ni (ClO)4)2·6H2One or more of O, preferably NiCl2·6H2O and/or Ni (ClO)4)2·6H2O。
In the invention, when the catalyst further comprises a reducing agent, the molar ratio of the olefin shown as the formula I to the reducing agent can be 1: 0.01-10, and preferably 1: 0.2-1.
In the present invention, the molar ratio of the olefin represented by formula I to the nickel compound may be 1:0.01 to 1, preferably 1:0.03 to 0.06, for example, 1: 0.05.
In the present invention, the molar ratio of the nickel compound to the phosphine ligand may be 1:1 to 10, preferably 1:1.1 to 2, more preferably 1:1.1 to 1.4, for example 1: 1.2.
In the present invention, the molar ratio of the olefin represented by formula I to the cyanation reagent may be 1: 0.1-10, preferably 1: 0.5-0.8, such as 1:0.6, 1: 0.8.
In the present invention, the molar concentration of the olefin represented by formula I in the organic solvent may be 0.01 to 1mmol/m L, preferably 0.1 to 0.4mmol/m L, for example 0.2mmol/m L.
In the present invention, the molar ratio of the olefin represented by formula I to water may be 1: 1-10, preferably 1: 1-6, such as 1:1.3, 1:2.3 or 1 (529/90).
In the present invention, the temperature of the reduction reaction can be conventional in the art, for example, 20 to 100 ℃, preferably 50 to 80 ℃.
In the invention, when the phosphine ligand is 1, 3-bis (diphenylphosphino) propane, N-Dimethylpyridine (DMAP) can be added as an additive in the reduction reaction; the molar ratio of the olefin shown in the formula I to the N, N-dimethylpyridine can be 1: 0.1-3, preferably 1: 0.8-1.2, such as 1:1.
In the present invention, the progress of the reduction reaction can be monitored by a conventional monitoring method in the art (e.g. T L C, HP L C or NMR), and the reaction is generally terminated when the olefin shown in formula I disappears or does not react any more, and the reaction time is preferably 0.1 to 200 hours, more preferably 3 to 24 hours, such as 3.5 hours, 4 hours, 6 hours, 8 hours, 12 hours or 24 hours.
In the present invention, after the reduction reaction is completed, a post-treatment step may be further preferably included. The conditions and operation of said work-up are the same as those of the work-up customary in this type of reaction of the state of the art, comprising the following steps: and after the reaction is finished, filtering, removing the solvent, and separating and purifying. The filtration conditions and operations are the same as those conventional in this type of reaction in the art. The conditions and operations for removing the solvent may be those conventional in the art, such as concentration under reduced pressure. The conditions and operations for the separation and purification may be those conventional in the art, such as column chromatography, and the eluent for the column chromatography is preferably a mixed solvent of an alkane solvent (such as petroleum ether) and an ester solvent (such as ethyl acetate), and the volume ratio of the alkane solvent to the ester solvent is preferably 100:1 to 0:1, and more preferably 50:1 to 0: 1.
The invention also provides an olefin compound shown as the formula I-1, which has the following structure:
the reagents and starting materials used in the present invention are commercially available unless otherwise specified.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The positive progress effects of the invention are as follows: the preparation method provided by the invention uses the cheap and easily-obtained nickel compound as the catalyst, and safely, mildly and efficiently realizes the reaction of olefin and a cyanation reagent to prepare the alkyl nitrile compound. The preparation method avoids the use of hydrogen cyanide or acetone cyanohydrin with high toxicity in the traditional synthetic method, and the prepared alkyl nitrile has good yield and stereoselectivity and is greatly improved in the aspects of functional group compatibility and substrate universality. In addition, the preparation method of the invention uses water as a hydrogen source, and has the advantages of green and economy.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Preparation of example 1
Methyltriphenylphosphonium bromide (2.14g,6mmol) was dissolved in dry tetrahydrofuran (10ml) under argon and KO was added theretotBu (785.5mg,7mmol), stirring the reaction solution at room temperature for 30 min, cooling to-78 deg.C, adding dropwise 3, 5-dimethoxybenzaldehyde (830.9mg,5mmol) tetrahydrofuran (5m L) solution, stirring for 12h after the reaction returns to room temperature, adding 2m L methanol to quench the reaction, concentrating the reaction solution, purifying by silica gel column chromatography, eluting with 811mg of colorless liquid (yield 99%),1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):3.79(s,6H),5.24(d,J＝10.8Hz,1H),5.72(dd,J＝17.6,0.8Hz,1H),6.38(t,J＝2.4Hz,1H),6.56(d,J＝2.4Hz,2H),6.64(dd,J＝17.6,10.8Hz,1H).13C NMR(100M，CDCl3):55.23，99.97，104.20，114.27，136.78，139.53，160.83.
Preparation of example 2
Methyltriphenylphosphonium bromide (1.7861g,5mmol) was dissolved in dry tetrahydrofuran (25m L) under argon and cooled to 0 deg.CnBu L i (2M L, 2.5M in hexane,5mmol) and stirring at this temperature was continued for 2h, a solution of benzothiophene-2-carboxaldehyde (811.1mg,5mmol) in tetrahydrofuran (4M L) was added thereto, the reaction was stirred at room temperature for 4h, quenched with water, extracted with diethyl ether, washed with water and saturated NaCl, anhydrous Na2SO4Drying, filtering, concentrating, and purifying by silica gel column chromatography. Eluent: petroleum ether/ethyl acetate 10:1, white solid 665mg, yield 83%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):5.28(d,J＝10.8Hz,1H),5.65(d,J＝17.2Hz,1H),6.89(dd,J＝17.2,10.8Hz,1H),7.13(s,1H),7.25-7.31(m,2H),7.65-7.67(m,1H),7.73-7.75(m,1H).13C NMR(100M,CDCl3):115.89,122.21,123.03,124.35,124.72,130.53,138.77,139.94,143.03.
Preparation of example 3
Dissolving formononetin (2.68g,10mmol) and triethylamine (2.02g,20mmol) in dichloromethane (50m L) under argon protection, cooling to 0 deg.C, and adding Tf2O (3.10g,11mmol), and after the addition was complete, the reaction was allowed to return to room temperature for 2 h. With saturated NH4The reaction was quenched with Cl and extracted with dichloromethane. The organic phases were combined and washed with anhydrous Na2SO4Drying, filtering, concentrating and purifying by column chromatography, wherein an eluent: petroleum ether/dichloromethane ═ 1:2, obtaining the intermediate formononetin protected by trifluoromethanesulfonyl, wherein the product is 2.76g of white solid, the yield is 69 percent,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):3.84(s,3H),6.97(d,J＝8.8Hz,2H),7.33(dd,J＝8.8,2.4Hz,1H),7.45(d,J＝2.0Hz,1H),7.49(d,J＝8.8Hz,2H),8.01(s,1H),8.40(d,J＝8.8Hz,1H).13C NMR(100M,CDCl3):55.26,111.39,114.04,118.47,118.63(q,1JC-F＝321.3Hz),123.08,124.14,125.62,129.12,130.00,152.02,152.80,156.27,159.86,175.11.19F NMR(400M,CDCl3):-72.61.
Under the protection of argon, collecting formononetin (1.2010g,3mmol) protected by trifluoromethanesulfonyl, Pd (PPh)3)2Cl2(210.6mg,0.3mmol) and L iCl (127.2mg,3mol) were dissolved in DMF (18M L) to which tributylvinyltin (1.0464g,3.3mmol) was added dropwise, after the addition was completed, the mixture was put in a 90 ℃ oil bath and added to react for 4h, after the reaction was completed, the reaction solution was cooled to room temperature, diluted with diethyl ether and then with 1M HCl solution, saturated NaHCO3The solution was washed with saturated NaCl solution and the combined aqueous phases were extracted once more with ether. The organic phases were combined and anhydrous Na2SO4Washing, filtering, concentrating, and purifying by silica gel column chromatography. Eluent: petroleum ether/dichloromethane/ethyl acetate ═ 6: 1:1, the obtained target product is 637.7mg of white solid, the yield is 76 percent,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):3.83(s,3H),5.48(d,J＝11.2Hz,1H),5.94(d,J＝17.6,Hz,1H),6.79(dd,J＝17.6,11.2Hz,1H),6.96-6.98(m,1H),7.41(s,1H),7.46-7.52(m,3H),7.96(s,1H),8.24(d,J＝8.4Hz,1H).13C NMR(100M,CDCl3):55.26,113.91,115.37,117.81,122.83,123.62,124.03,124.97,126.49,130.02,135.32,142.89,152.49,156.44,159.55,176.06.IR(neat):3092,3076,3040,3011,2972,2930,2838,1624,1609,1557,1513,1439,1407,1358,1291,1253,1233,1176,1106,1024,985,927,901,886,878,830,821,802,791,767,717cm-1HRMS (ESI) calculated value C18H15O3[M+H]+279.1016, found 279.1007.
Preparation of example 4
Under the protection of argon, estrone (2.70g,10mmol) and triethylamine (2.02g,20mmol) were dissolved in dichloromethane (50m L), cooled to 0 ℃ and Tf was added thereto2O (3.10g,11mmol), and after the addition was complete, the reaction was allowed to return to room temperature for 3 h. With saturated NH4The reaction was quenched with Cl and extracted with dichloromethane. The organic phases were combined and washed with anhydrous Na2SO4Drying, filtering, concentrating, and purifying by column chromatographyEluent: petroleum ether/ethyl acetate 5:1, obtaining the intermediate compound of the estrone protected by trifluoromethanesulfonyl, wherein the product is 3.56g of white solid, the yield is 89 percent,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):0.92(s,3H),1.44-1.70(m,6H),1.96-2.20(m,4H),2.27-2.35(m,1H),2.38-2.43(m,1H),2.52(dd,J＝18.6,8.8Hz,1H),2.93-2.96(m,2H),6.99-7.00(m,1H),7.04(dd,J＝8.6,2.4Hz,1H),7.35(d,J＝8.4Hz,1H).13C NMR(100M,CDCl3):13.68,21.46,25.58,25.98,29.28,31.39,35.70,37.65,44.00,47.75,50.28,118.19,118.66(1JC-F＝320.5Hz),121.13,127.11,139.24,140.22,147.51,220.30.19F NMR(400M,CDCl3):-73.03.
Under the protection of argon, collecting estrenol ketone protected by trifluoromethanesulfonyl (1.2073g,3mmol), Pd (PPh)3)2Cl2(210.6mg,0.3mmol) and L iCl (127.2mg,3mol) were dissolved in DMF (18M L) to which tributylvinyltin (1.0464g,3.3mmol) was added dropwise, after the addition was completed, the mixture was put in a 90 ℃ oil bath and added to react for 4h, after the reaction was completed, the reaction solution was cooled to room temperature, diluted with diethyl ether and then with 1M HCl solution, saturated NaHCO3The solution was washed with saturated NaCl solution and the combined aqueous phases were extracted once more with ether. The organic phases were combined and anhydrous Na2SO4Washing, filtering, concentrating, and purifying by silica gel column chromatography. Eluent: dichloromethane to obtain the target product as white solid 650.0mg with 77% yield,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):0.90(s,3H),1.38-1.67(m,6H),1.94-2.18(m,4H),2.25-2.31(m,1H),2.39-2.44(m,1H),2.50(dd,J＝18.8,8.4Hz,1H),2.89-2.93(m,2H),5.19(d,J＝11.2Hz,1H),5.70(d,J＝17.6Hz,1H),6.66(dd,J＝17.6,10.8Hz,1H),7.14(s,1H),7.19-7.26(m,2H).13C NMR(100M,CDCl3):13.77,21.51,25.63,26.41,29.31,31.50,35.78,38.06,44.35,47.90,50.39,113.11,123.52,125.47,126.80,135.10,136.48,139.44.
Preparation of example 5
Phenylpropanal (1.34g,10mmol) was dissolved in tetrahydrofuran (20M L) under argon, cooled to 0 deg.C, vinyl magnesium bromide (12M L, 1M in THF,12mmol) was added dropwise thereto, and after completion of addition, the reaction was allowed to return to room temperature for 3h4The reaction was quenched with Cl solution and extracted with ethyl acetate. The organic phases were combined and washed with water and saturated NaCl. Anhydrous Na2SO4Drying, filtering and concentrating, and carrying out silica gel column chromatography, and eluting: petroleum ether/ethyl acetate 10:1, the product is colorless liquid 1.34g, the yield is 83 percent,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3):1.76(s,1H),1.82-1.87(m,2H),2.64-2.78(m,2H),4.12(q,J＝6.4Hz,1H),5.13(d,J＝10.4Hz,1H),5.23(d,J＝17.2Hz,1H),5.89(ddd,J＝17.2,10.4,6.4Hz,1H),7.16-7.23(m,3H),7.28(t,J＝7.2Hz,2H)；13C NMR(100MHz,CDCl3):31.56,38.44,72.40,114.89,125.80,128.34,128.41,140.94,141.82.
Preparation of example 6
Dissolving 5-phenylpent-1-en-3-ol (486.7mg,3mmol) in dichloromethane (20m L) in air, adding imidazole (408.5mg,6mmol) and tert-butyldimethylsilyl chloride (678.2mg,4.5mmol), reacting at room temperature for 2h after the addition, filtering the reaction solution with diatomite, washing with dichloromethane, concentrating the filtrate, purifying by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (50: 1), the product is a colorless liquid (722.1 mg), with the yield of 87%,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3):0.08(s,3H),0.10(s,3H),0.96(s,9H),1.78-1.92(m,2H),2.62-2.76(m,2H),4.17-4.22(m,1H),5.10(dd,J＝10.4,1.2Hz,1H),5.21(dd,J＝17.4,1.2Hz,1H),5.84-5.92(m,1H),7.19-7.22(m,3H),7.29-7.32(m,2H)；13C NMR(100MHz,CDCl3):-4.82,-4.33,18.25,25.89,31.45,39.81,73.33,113.95,125.65,128.30,128.37,141.43,142.46.
EXAMPLE 1 Compound (1a)
In a glove box filled with nitrogen, NiCl was sequentially added to a 8.0m L reaction flask2·6H2O(0.025mmol,5.9mg),Xantphos(0.03mmol,17.4mg),Zn(0.1mmol,6.5mg),Zn(CN)2(0.3mmol,35.2mg), p-methylstyrene (0.5mmol,59.1mg) and 1, 4-dioxane (2.5m L), then the reaction flask is covered tightly and removed from the glove box, water (50 mu L) is added by a syringe, then the reaction is put into an oil bath which is preheated to 80 ℃ for reaction, the reaction is stopped after 4 hours, after the reaction liquid is cooled to room temperature, silica gel is filtered, ethyl acetate is washed, the filtrate is concentrated and is directly purified by silica gel column chromatography, an eluent, petroleum ether/ethyl acetate (100: 1 to 50: 1) is eluted, the product is 67.5mg of colorless oily liquid, the yield is 93 percent,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.62(d,J＝7.2Hz,3H),2.35(s,3H),3.86(q,J＝7.2Hz,1H),7.18(d,J＝8.0Hz,2H),7.25(d,J＝8.4Hz,2H).13C NMR(100M,CDCl3):20.98,21.44,30.80,121.73,126.52,129.71,134.05,137.78.
EXAMPLE 2 Compound (1b)
The operating technique of example 2 employed the operation of example 1, with the exception that only the olefin feed was used.
By adopting the scheme of example 1, styrene is used as a raw material, silica gel column chromatography is adopted for purification, and eluent: eluting with 50:1 petroleum ether/ethyl acetate to obtain 57.4mg colorless oily liquid with 88% yield,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.62(d,J＝7.2Hz,3H),3.89(q,J＝7.2Hz,1H),7.29-7.40(m,5H).13C NMR(100M,CDCl3):21.34,31.09,121.51,126.58,127.92,129.02,136.96.
EXAMPLE 3 Compound (1c) and Compound (2c)
Under the condition of filling with nitrogenIn an atmospheric glove box, NiCl was added sequentially to a 8.0m L reaction flask2·6H2O(0.025mmol,5.9mg),dppf(0.03mmol,16.6mg),Zn(0.5mmol,32.7mg),Zn(CN)2(0.3mmol,35.2mg), o-methylstyrene (0.5mmol,59.1mg) and 1, 4-dioxane (2.5m L), then the reaction flask is covered tightly and removed from the glove box, water (50 mu L) is added by a syringe, then the reaction flask is put into an oil bath preheated to 80 ℃ for reaction, the reaction is stopped after 4 hours, after the reaction solution is cooled to room temperature, silica gel is filtered, ethyl acetate is washed, the filtrate is concentrated and is directly purified by silica gel column chromatography, an eluent, petroleum ether/ethyl acetate (50: 1 to 20: 1) is eluted in a gradient manner, the product 1c is colorless oily liquid 46.0mg, the yield is 63 percent,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.60(d,J＝7.2Hz,3H),2.35(s,3H),4.03(q,J＝7.2Hz,1H),7.17-7.27(m,3H),7.43-7.45(m,1H).13C NMR (100M, CDCl3):18.90,19.93,28.05,121.72,126.59,126.88,128.02,130.90,134.69,135.17. The product 2c was 7.0mg of a colorless oily liquid, the yield was 10%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):2.33(s,3H),2.58(t,J＝7.6Hz,2H),2.98(t,J＝7.6Hz,2H),7.15-7.20(m,4H).13C NMR(100M,CDCl3):17..97,19.14,28.84,119.19,126.45,127.33,128.67,130.61,135.74,136.18.
EXAMPLE 4 Compound (1d)
The experimental techniques of examples 4-21 all used the operating technique of example 1, with only the olefin feedstock being used and the reaction time or separation method may vary from one example to another.
By adopting the scheme of example 1, the method takes the p-isobutylstyrene as the raw material, the reaction time is 6 hours, and the plate chromatography purification is prepared, and the developing agent: the product was 70.0mg of colorless oily liquid eluted at 50:1 with a yield of 75%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):0.90(d,J＝6.8Hz,6H),1.62(d,J＝7.6Hz,3H),1.80-1.90(m,1H),2.47(d,J＝7.2Hz,2H),3.86(q,J＝7.2Hz,1H),7.14(d,J＝8.0Hz,2H),7.25(d,J＝8.0Hz,2H).13C NMR(100M,CDCl3):21.34,22.22,30.09,30.78,44.85,121.73,126.34,129.72,134.22,141.53.
EXAMPLE 5 Compound (1e)
By adopting the scheme of the embodiment 1, the p-methoxystyrene is taken as a raw material, the reaction time is 4 hours, the silica gel column chromatography is adopted for purification, and the eluent: the product was 73.9mg of colorless oily liquid eluted at 30:1 with a yield of 92%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.60(d,J＝7.6Hz,3H),3.80(s,3H),3.84(q,J＝7.8Hz,1H),6.89-6.92(m,2H),7.25-7.27(m,2H).13C NMR(100M,CDCl3):21.39,30.31,55.22,114.36,121.79,127.72,128.98,159.18.
EXAMPLE 6 Compound (1f)
The scheme of example 1 is adopted, 3, 5-dimethoxy styrene is used as a raw material, the reaction time is 4 hours, silica gel column chromatography purification is carried out, and eluent: the product was 91.3mg of colorless oily liquid eluted at 30:1 with a yield of 95%,1the purity of HNMR is more than 98 percent.1H NMR(400M,CDCl3):1.62(d,J＝7.2Hz,3H),3.79-3.84(m,7H),6.40(t,J＝2.0Hz,1H),6.49(d,J＝2.0Hz,2H).13C NMR(100M,CDCl3):21.12,31.19,55.24,99.52,104.75,121.35,139.12,161.14.IR(neat):2985,2941,2839,2242,1596,1457,1429,1349,1328,1296,1204,1152,1051,836,735,694cm-1HRMS (ESI) calculated value C11H14NO2[M+H]+192.1019, found 192.1017.
EXAMPLE 7 Compound (1g)
By adopting the scheme of the embodiment 1, the p-hydroxystyrene is taken as a raw material, the reaction time is 4 hours, the silica gel column chromatography is used for purification, and the eluent: gradient elution with petroleum ether to petroleum ether/ethyl acetate from 5:1 to 3:1, the product being 63.7mg of colorless oily liquid, yield 87%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.59(d,J＝7.6Hz,3H),3.84(q,J＝7.2Hz,1H),6.59(s,1H),6.82-6.86(m,2H),7.17(d,J＝8.8Hz,2H).13C NMR(100M,CDCl3):21.21,30.30,115.97,121.95,127.88,128.44,155.67.IR(neat):3344,3022,2988,2936,2254,1613,1591,1515,1441,1372,1356,1343,1274,1264,1216,1185,1175,1107,1083,1054,987,837,818,732cm-1HRMS (EI) calculation C9H9NO[M]+147.0684, found 147.0679.
EXAMPLE 8 Compound (1h)
By adopting the scheme of the embodiment 1, the p-amino styrene is taken as a raw material, the reaction time is 4 hours, the silica gel column chromatography is used for purification, and the eluent: petroleum ether/ethyl acetate 1:1, 64.7mg of light yellow oily liquid as the product, 89% yield,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.56(d,J＝7.2Hz,3H),3.72(s,2H),3.76(q,J＝7.2Hz,1H),6.64(d,J＝8.4Hz,2H),7.09(d,J＝8.8Hz,2H).13C NMR(100M,CDCl3):21.25,30.19,115.20,122.10,126.39,127.46,146.18.IR(neat):3460,3369,3325,2983,2924,2853,2238,1623,1516,1452,1378,1285,1183,1130,1084,988,826cm-1HRMS (ESI) calculated value C9H11N2[M]+147.0917, found 147.0914.
Example 9 Compound (1i)
By adopting the scheme of the embodiment 1, p-fluorostyrene is taken as a raw material, the reaction time is 4 hours, silica gel column chromatography purification is carried out,eluent: gradient elution with petroleum ether/ethyl acetate 40:1 to 20:1, 60.4mg of colorless oily liquid as the product, 81% yield,1the purity of HNMR is more than 98 percent.1H NMR(400M,CDCl3):1.63(d,J＝7.2Hz,3H),3.90(q,J＝7.2Hz,1H),7.05-7.09(m,2H),7.31-7.35(m,2H).13C NMR(100M,CDCl3):21.37,30.44,115.97(2JC-F＝22.1Hz),121.34,128.35(3JC-F＝8.4Hz),132.77(4JC-F＝3.8Hz),162.22(1JC-F＝247.3Hz).19F NMR(400M,CDCl3):-114.02～113.95(m).
EXAMPLE 10 Compound (1j)
The scheme of example 1 is adopted, p-trifluoromethylstyrene is taken as a substrate, and the reaction time is 4 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 30:1, 84.0mg of the product as a colorless oily liquid, yield 84%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.67(d,J＝7.2Hz,3H),3.99(q,J＝7.2Hz,1H),7.50(d,J＝8.0Hz,2H),7.66(d,J＝8.0Hz,2H).13C NMR(100M,CDCl3):21.13,31.01,120.72,123.75(q,1JC-F＝272.4Hz),126.08(q,3JC-F＝3.8Hz),127.15,130.35(q,2JC-F＝32.9Hz),140.95(q,5JC-F＝1.5Hz).19F NMR(400M,CDCl3):-62.76.
EXAMPLE 11 Compound (1k)
The scheme of example 1 is adopted, p-cyanostyrene is used as a raw material, and the reaction time is 4 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 10:1, 66.2mg of the product as colorless oily liquid, yield 85%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.68(d,J＝7.6Hz,3H),4.02(q,J＝7.2Hz,1H),7.52(d,J＝8.4Hz,2H),7.71(d,J＝8.4Hz,2H).13C NMR(100M,CDCl3):20.93,31.11,112.01,118.01,120.26,127.52,132.81,142.00.
EXAMPLE 12 Compound (1l)
The scheme of example 1 is adopted, para-plate pinacol borate substituted styrene is used as a raw material, and the reaction time is 4 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 30:1 to 10:1, 98.8mg of white solid, yield 77%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.34(s,12H),1.62(d,J＝7.2Hz,3H),3.90(q,J＝7.2Hz,1H),7.36(d,J＝7.6Hz,2H),7.83(d,J＝7.6Hz,2H).13C NMR(100M,CDCl3):21.29,24.72,31.23,83.82,121.24,125.91,135.47,139.88.IR(neat):2983,2920,2239,1614,1521,1454,1412,1398,1358,1333,1282,1267,1167,1138,1094,1021,963,856,833,675,656cm-1HRMS (ESI) calculated value C15H24O2N2 10B[M+NH4]+274.1962, found 274.1961.
Example 13 Compound (1m)
The scheme of example 1 is adopted, 4-vinyl biphenyl is used as a raw material, and the reaction time is 4 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 40:1 to 20:1, 98.3mg of white solid, yield 95%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.63(d,J＝7.2Hz,3H),3.90(q,J＝7.2Hz,1H),7.32-7.44(m,5H),7.57(t,J＝8.4Hz,4H).13C NMR(100M,CDCl3):21.26,30.76,121.47,126.93,127.03,127.48,127.67,128.74,135.89,140.07,140.88.
Example 14 Compound (1n)
The scheme of example 1 is adopted, 2-vinyl naphthalene is used as a raw material, and the reaction time is 4 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 40:1 to 20:1, 82.4mg of white solid as product, 91% yield,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.66(d,J＝7.2Hz,3H),3.99(q,J＝7.2Hz,1H),7.37(dd,J＝8.6,2.0Hz,1H),7.45-7.50(m,2H),7.79-7.83(m,4H).13C NMR(100M,CDCl3):21.22,31.20,121.50,124.26,125.41,126.33,126.57,127.57,127.70,128.98,132.60,133.14,134.19.
EXAMPLE 15 Compound (1o)
The scheme of example 1 is adopted, 2-methoxy-6-vinyl naphthalene is used as a raw material, and the reaction time is 8 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 30:1, 103.7mg of white solid, 98% yield,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.65(d,J＝7.6Hz,3H),3.87(s,3H),3.95(q,J＝7.2Hz,1H),7.09(d,J＝2.0Hz,1H),7.15(dd,J＝9.0,2.0Hz,1H),7.34(dd,J＝8.4,1.2Hz,1H),7.67-7.72(m,3H).13C NMR(100M,CDCl3):21.19,30.98,55.12,105.49,119.37,121.65,124.75,125.18,127.72,128.57,129.12,131.85,133.83,157.90.
EXAMPLE 16 Compound (1p)
The scheme of example 1 is adopted, 3-vinyl pyridine is used as a raw material, and the reaction time is 4 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 1:1, 54.6mg of product as colorless liquid, yield 83%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.68(d,J＝7.2Hz,3H),3.98(q,J＝7.2Hz,1H),7.34-7.37(m,1H),7.75(d,J＝8.0Hz,1H),8.60-8.62(m,2H).13C NMR(100M,CDCl3):20.99,28.78,120.42,123.74,132.72,134.12,148.02,149.34.IR(neat):3037,2988,2941,2243,1577,1481,1455,1426,1301,1181,1129,1089,1043,1027,990,810,711cm-1HRMS (ESI) calculated value C8H9N2[M+H]+133.0760, found 133.0758.
EXAMPLE 17 Compound (1q)
The scheme of example 1 is adopted, 3-vinyl indole is used as a raw material, and the reaction time is 8 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 10:1, 73.8mg of colorless liquid as the product, 87% yield,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.67(d,J＝7.2Hz,3H),4.08(q,J＝7.2Hz,1H),7.04(d,J＝1.6Hz,1H),7.12-7.22(m,2H),7.31(d,J＝8.0Hz,1H),7.62(d,J＝8.0Hz,1H),8.28(s,1H).13C NMR(100M,CDCl3):19.39,22.66,111.36,111.62,118.17,119.86,121.66,121.98,122.50,124.94,136.33.IR(neat):3409,3063,2983,2943,2240,1618,1457,1421,1355,1339,1248,1225,1100,1032,1012,909,819,765,739cm-1HRMS (EI) calculation C11H10N2[M]+170.0844, found 170.0842.
Example 18 Compound (1r)
The scheme of example 1 is adopted, and the reaction time is 8 hours by using 2-vinylbenzothiophene. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 30:1, 79.0mg of white solid, yield 84%,1h NMR purity was greater than 98%.1HNMR(400M,CDCl3):1.73(d,J＝7.2Hz,3H),4.16(q,J＝7.2Hz,1H),7.27-7.36(m,3H),7.69-7.71(m,1H),7.76(d,J＝7.6Hz,1H).13C NMR(100M,CDCl3):20.87,27.20,120.09,122.11,122.17,123.58,124.63,124.69,138.96,139.24,139.66.IR(neat):3056,2993,2983,2938,2925,2241,1459,1435,1376,1205,1156,1143,1129,1057,967,943,876,841,823,728,679,666cm-1HRMS (EI) calculation C11H9NS[M]+187.0456, found 187.0459.
EXAMPLE 19 Compound (1s)
The scheme of example 1 is adopted, the formononetin derivative alkene is used as a raw material, and the reaction time is 4 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 3:1, 131.0mg of white solid, 86% yield,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.70(d,J＝7.2Hz,3H),3.82(s,3H),4.05(q,J＝7.2Hz,1H),6.96(d,J＝8.8Hz,2H),7.37(d,J＝8.4Hz,1H),7.49(d,J＝8.8Hz,3H),7.99(s,1H),8.29(d,J＝8.4Hz,1H).13C NMR(100M,CDCl3):20.99,31.04,55.16,113.83,116.18,120.41,123.54,123.84,125.04,127.38,129.89,142.81,152.51,156.09,159.54,175.66.IR(neat):3081,2961,2937,2909,2833,2246,1637,1624,1606,1574,1562,1511,1437,1371,1357 1289,1246,1229,1195,1178,1116,1107,1028,902,887,837,818,805,789,701cm- 1HRMS (ESI) calculated value C19H16NO3[M+H]+306.1125, found 306.1117.
EXAMPLE 20 Compound (1t)
The protocol of example 1 was used starting with an estrone-derived olefin and a reaction time of 4 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 3:1, 146.0mg of product as pale yellow solid, yield 95%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):0.91(s,3H),1.40-1.67(m,9H),1.95-2.19(m,4H),2.26-2.31(m,1H),2.39-2.44(m,1H),2.50(dd,J＝18.6,8.6Hz,1H),2.91-2.95(m,2H),3.84(q,J＝7.2Hz,1H),7.10-7.13(m,2H),7.30(d,J＝7.6Hz,1H).13C NMR(100M,CDCl3):13.62,21.20,21.23,21.35,25.46,26.13,29.12,29.15,30.50,30.52,31.33,35.62,37.78,44.02,47.71,50.21,121.57,123.85,125.94,127.03,134.29,134.31,137.26,139.47,220.51.IR(neat):3369,2927,2859,2239,1732,1498,1454,1404,1373,1243,1086,1050,1008,819cm-1HRMS (ESI) calculated value C21H25NO[M]+307.1936, found 307.1943.
Example 21 Compound (1u)
The scheme of example 1 was adopted, 4-phenyl-1, 3-butadiene was used as a substrate, and the reaction time was 24 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 50:1, 63.0mg of the product as a colorless liquid, yield 80%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.49(d,J＝6.8Hz,3H),3.45-3.52(m,1H),6.06(dd,J＝15.8,6.4Hz,1H),6.71(d,J＝16.0Hz,1H),7.24-7.38(m,5H).13C NMR(100M,CDCl3):18.95,28.27,120.81,124.23,126.45,128.17,128.63,132.41,135.60.
Example 22 Compound (3a)
In a glove box filled with nitrogen, NiCl was sequentially added to a 8.0m L reaction flask2·6H2O(0.025mmol,5.9mg),dppf(0.03mmol,16.6mg),Zn(0.1mmol,6.5mg),Zn(CN)2(0.3mmol,35.2mg), N-vinylpyrrolidone (0.5mmol,55.6mg) and acetonitrile (2.5m L), removing the reaction flask with a tight cover from the glove box, adding water (18 mu L) by using an injector, placing the reaction flask in an oil bath preheated to 80 ℃ for reaction, stopping the reaction after 12 hours, cooling the reaction solution to room temperature, filtering the silica gel, washing the reaction solution with ethyl acetate, concentrating the filtrate, and directly purifying the reaction solution by silica gel column chromatography, wherein the eluent is ethyl acetateThe product is 55.4mg of colorless oily liquid after removal, the yield is 80 percent,1h NMR purity was greater than 98%.1HNMR(400M,CDCl3):2.06-2.14(m,2H),2.41(t,J＝8.0Hz,2H),2.64(t,J＝6.4Hz,2H),3.55-3.59(m,4H).13C NMR(100M,CDCl3):16.39,17.98,30.43,38.82,47.87,117.96,175.44.
EXAMPLE 23 Compound (3b)
The operating techniques of examples 23 to 27 are almost identical to those of example 22, using only different olefins as starting materials.
The procedure of example 22 was followed, using N-vinylcarbazole as starting material and a reaction time of 12 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 5:1, 106.8mg of white solid as product, 97% yield,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):2.62(t,J＝7.2Hz,2H),4.41(t,J＝7.2Hz,2H),7.20-7.28(m,4H),7.41(t,J＝7.6Hz,2H),8.03(d,J＝7.6Hz,2H).13C NMR(100M,CDCl3):17.02,38.54,108.09,117.35,119.75,120.50,123.09,125.99,139.34.IR(neat):3045,2956,2930,2244,1593,1485,1459,1419,1383,1353,1333,1327,1261,1225,1198,1152,1123,1066,744,724cm-1HRMS (EI) calculation C15H13N2[M]+220.1000, found 220.1005.
Example 24 Compound (3c)
Using the protocol of example 22, starting from vinyl tert-valerate, the reaction time is 12 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 10:1, 41.1mg of product as colorless liquid, yield 53%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.24(s,9H),2.72(t,J＝6.4Hz,2H),4.27(t,J＝6.4Hz,2H).13C NMR(100M,CDCl3):17.89,26.95,38.69,58.43,116.68,177.91.
EXAMPLE 25 Compound (3d)
Using the protocol of example 22, starting from phenyl vinyl sulfone, the reaction time is 12 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 2:1, 84.0mg of white solid as product, 86% yield,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):2.81(t,J＝7.6Hz,2H),3.41(t,J＝7.6Hz,2H),7.62(t,J＝7.6Hz,2H),7.72(t,J＝7.6Hz,1H),7.93(d,J＝7.6Hz,2H).13C NMR(100M,CDCl3):11.79,50.75,116.09,128.04,129.57,134.51,137.27.
EXAMPLE 26 Compounds (3e) and (4e)
Using the protocol of example 22, dimethylphenylvinylsilane was used as starting material and the reaction time was 12 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 30:1 gave a mixture of product 3e and 4e (3e:4 e: 16.7:1) as a colourless liquid 81.3mg, total yield 86%. Where 3e has the following nuclear magnetism:1H NMR(400M,CDCl3):0.34(s,6H),1.11-1.15(m,2H),2.22-2.26(m,2H),7.35-7.38(m,3H),7.47-7.49(m,2H)13C NMR(100M,CDCl3) 3.67,11.77,11.95,121.02,127.95,129.41,133.76,136.46,17.02,38.54,108.09,117.35,119.75,120.50,123.09,125.99,139.34 partial nuclear magnetization of the other isomer 4e is as follows: partial1H NMR(400M,CDCl3):0.28(d,J＝0.8Hz,6H),1.22(d,J＝7.2Hz,3H),1.98(q,J＝7.2Hz,1H),7.54-7.57(m,2H).Partial13C NMR(400M,CDCl3):-5.69,-5.09,11.43,11.86,128.02,130.04,133.76.
Example 27 Compound (3f)
Using the protocol of example 22, diethyl allylphosphate was used as starting material and the reaction time was 12 hours. Silica gel column chromatography purification, eluent: ethyl acetate, 86.9mg of a colorless liquid as a product, 85% yield,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.34(t,J＝7.2Hz,6H),1.85-2.03(m,4H),2.52(t,J＝6.8Hz,2H),4.07-4.17(m,4H).13C NMR(100M,CDCl3):16.17(d,3JC-P＝5.7Hz),17.46(d,2JC-P＝15.4Hz),18.90(d,3JC-P＝4.5Hz),24.20(d,1JC-P＝142.6Hz),61.59(d,2JC-P＝6.1Hz),118.63.31P NMR(400M,CDCl3):29.28.IR(neat):3458,2979,2927,2909,2244,1233,1163,1024,957,784,733cm-1HRMS (ESI) calculation for C8H20N2O3P[M+NH4]+223.1206, measurement 223.1201.
EXAMPLE 28 Compound (5a) and Compound (6a)
Ni (ClO) was sequentially added to a 8.0m L reaction flask in a glove box filled with nitrogen gas4)2·6H2O(0.025mmol,9.1mg),dppp(0.03mmol,14.8mg),Zn(0.5mmol,32.7mg),Zn(CN)2(0.3mmol,35.2mg), DMAP (0.5mmol,61.1mg), 2-allylnaphthalene (0.5mmol,84.1mg) and acetonitrile (2.5m L), then the reaction flask was taken out of the glove box with the cover closed and water (18. mu. L) was added with a syringe, then placed in an oil bath preheated to 80 ℃ for reaction, the reaction was stopped after 24 hours, after the reaction liquid was cooled to room temperature, silica gel was filtered, ethyl acetate was washed, the filtrate was concentrated, and direct preparative plate chromatography was performed for purification, eluent petroleum ether/ethyl acetate 30:1 developed, product 5a was 8.8mg as a white solid, yield 9%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.36(d,J＝6.8Hz,3H),2.92-3.01(m,2H),3.09-3.14(m,1H),7.34(dd,J＝8.6,1.6Hz,1H),7.46-7.49(m,2H),7.69(s,1H),7.80-7.83(m,3H).13C NMR(100M,CDCl3) 17.62,27.42,40.11,122.54,125.88,126.27,126.93,127.65,127.84,128.46,132.52,133.40,134.27 product 6a was 76.2mg of a white solid with a yield of 78%.1H NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.94-2.01(m,2H),2.23(t,J＝7.2Hz,2H),2.86(t,J＝7.2Hz,2H),7.25(dd,J＝8.2,1.6Hz,1H),7.39-7.46(m,2H),7.58(s,1H),7.75-7.79(m,3H).13C NMR(100M,CDCl3):16.16,26.55,34.27,119.40,125.40,126.05,126.66,127.31,127.50,128.20,132.06,133.37,137.02.
EXAMPLE 29 Compound (5b) and Compound (6b)
The procedure of example 28 was followed, using 4-allylanisole as starting material and a reaction time of 24 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 20:1, product 70.6mg of a mixture of 5b and 6b (6b:5 b-8.3: 1) was a colorless liquid with an overall yield of 81%. Wherein 6b has a nuclear magnetism as follows:1H NMR(400M,CDCl3):1.89-1.96(m,2H),2.28(t,J＝7.2Hz,2H),2.70(t,J＝7.2Hz,2H),3.78(s,3H),8.40(d,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,2H).13C NMR(100M,CDCl3) 16.10,26.95,33.29,55.09,113.89,119.47,129.25,129.95,131.58,158.08 partial nuclear magnetization of the other isomer 5b is as follows: partial1H NMR(400M,CDCl3):1.30(d,J＝6.4Hz,3H)，2.77-2.87(m,3H),3.78(s,3H),7.14(d,J＝8.8Hz,2H),partial13CNMR(400M,CDCl3):17.34,27.61,38.96,113.90.
EXAMPLE 30 Compound (5c) and Compound (6c)
The procedure of example 28 was followed, using 4-phenyl-1-butene as starting material and a reaction time of 4 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 30:1 to 20:1, product 5c was 9.2mg of colorless liquid, yield 12%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.33(d,J＝7.2Hz,3H),1.79-1.88(m,1H),1.91-2.01(m,1H),2.53-2.62(m,1H),2.71-2.79(m,1H),2.84-2.91(m,1H),7.19-7.26(m,3H),7.29-7.33(m,2H).13C NMR(100M,CDCl3) 17.97,24.81,33.15,35.71,122.74,126.38,128.38,128.61,140.11. product 6c is a colorless liquid 64.3mg, yield 81%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.62-1.69(m,2H),1.73-1.81(m,2H),2.31(t,J＝7.2Hz,2H),2.64(t,J＝7.2Hz,2H),7.15-7.21(m,3H),7.26-7.30(m,2H).13C NMR(100M,CDCl3):16.92,24.71,30.14,34.85,119.54,125.95,128.24,128.35,141.12.
EXAMPLE 31 Compound (5d) and Compound (6d)
The procedure of example 28 was followed, starting from 1-decene, in a reaction time of 24 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 5:1, product 64.7mg of a mixture of 5d and 6d (6b:5b 12.5:1) was a colourless liquid in 77% overall yield. Wherein the nuclear magnetization of 6d is as follows:1H NMR(400M,CDCl3):0.88(t,J＝6.8Hz,3H),1.20-1.32(m,12H),1.41-1.46(m,2H),1.62-1.69(m,2H),2.33(t,J＝7.2Hz,2H),3.64(t,J＝6.4Hz,2H).13C NMR(100M,CDCl3) 13.96,16.98,22.54,25.26,28.54,28.64,29.13,29.19,29.34,31.73,119.73 nuclear magnetization of part 5d is as follows: partial1H NMR(400M,CDCl3):0.88(t,J＝6.8Hz,3H)，2.55-2.64(m,1H),partial13C NMR(400M,CDCl3):17.90,25.38,26.91,28.95,29.05,29.20,31.69,33.95.
EXAMPLE 32 Compound (5e) and Compound (6e)
The procedure of example 28 was followed, using tert-butyldiphenylsilicon-protected 4-butenol as starting material, and the reaction time was 24 hours. Silica gel column chromatographyDissolving and eluting the mixture: petroleum ether/ethyl acetate 30:1, product 5e was 11.5mg as a colorless liquid, yield 7%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.06(s,9H),1.32(d,J＝7.2Hz,3H),1.68-1.79(m,1H),1.81-1.89(m,1H),2.92-3.01(m,1H),3.73-3.85(m,2H),7.37-7.46(m,6H),7.64(m,4H).13C NMR(100M,CDCl3):17.76,19.18,21.94,26.79,36.70,60.53,122.91,127.75,127.76,129.78,129.80,133.15,133.35,135.45,135.51.IR(neat):3071,2931,2857,2239,1587,1472,1428,1388,1110,998,981,902,822,738,700,687cm-1.HRMS(ESI)calcd for C21H31N2OSi[M+NH4]+355.2200, found 355.2196 product 6e was 124.3mg of a colorless liquid, 74% yield.1H NMR(400M,CDCl3):1.06(s,9H),1.64-1.71(m,2H),1.73-1.81(m,2H),2.30(t,J＝7.2Hz,2H),3.69(t,J＝6.0Hz,2H),7.35-7.43(m,6H),7.64-7.66(m,4H).13C NMR(100M,CDCl3):16.74,19.05,22.09,26.73,31.08,62.52,119.62,127.60,129.60,133.45,135.38.IR(neat):3071,3045,2931,2857,2244,1590,1472,1427,1385,1186,1109,1007,974,822,740,700,686cm-1.HRMS(ESI)calcd for C21H31N2OSi[M+NH4]+:355.2200,found 355.2199.
EXAMPLE 33 Compound (5f) and Compound (6f)
The procedure of example 28 was followed, using 5-penten-1-ol as starting material, for a reaction time of 24 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 3:1, product 5f and 6f mixture (6f:5f 9.1:1) was 50.4mg of colorless liquid in 89% overall yield. Wherein 6f has a nuclear magnetism as follows:1H NMR(400M,CDCl3):1.49-1.64(m,4H),1.67-1.74(m,2H),2.27(s,1H),2.38(t,J＝7.2Hz,2H),3.64(t,J＝6.4Hz,2H).13C NMR(100M,CDCl3) 16.98,24.85,25.01,31.53,61.98,119.68. the nuclear magnetization of fraction 5f is as follows: partial1H NMR(400M,CDCl3):1.34(d,J＝7.2Hz,3H),2.64-2.73(m,1H),partial13C NMR(400M,CDCl3):17.87,25.24,29.77,30.38,61.54.
EXAMPLE 34 Compound (5g) and Compound (6g)
Using the protocol of example 28, N-allylphthalimide was used as the substrate and the reaction time was 24 hours. Preparative plate chromatography purification, eluent: petroleum ether/ethyl acetate 5:1, product 5g as a white solid 18.2mg, yield 17%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.40(d,J＝6.8Hz,3H),3.19-3.28(m,1H),3.77(dd,J＝13.8,6.8Hz,1H),4.02(dd,J＝13.6,8.4Hz,1H),7.76-7.79(m,2H),7.87-7.91(m,2H).13CNMR(100M,CDCl3):15.54,25.23,40.09,120.37,123.68,131.59,134.40,167.69. The product 6g was 83.5mg of a colorless liquid, yield 78%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):2.05-2.12(m,2H),2.45(t,J＝7.2Hz,2H),3.82(t,J＝6.4Hz,2H),7.73-7.77(m,2H),7.84-7.88(m,2H).13C NMR(100M,CDCl3):14.95,24.60,36.50,118.70,123.30,131.70,134.11,168.10.
EXAMPLE 35 Compound (6h)
The procedure of example 28 was followed, starting from ethyl pentenoate, and the reaction time was 24 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 10:1 to 3:1, 57.5mg of product as colorless liquid, yield 74%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.26(t,J＝7.2Hz,3H),1.68-1.82(m,4H),2.34-2.41(m,4H),4.14(q,J＝7.2Hz,2H).13C NMR(100M,CDCl3):14.00,16.74,23.69,24.61,33.09,60.28,119.21,172.58.
Example 36 Compound (6i)
The procedure of example 28 was followed, starting from 1-undecenal, and the reaction time was 24 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 10:1, 57.1mg of product as colorless liquid, yield 58%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.26-1.30(m,10H),1.39-1.46(m,2H),1.59-1.69(m,4H),2.34(t,J＝7.2Hz,2H),2.41-2.45(m,2H),9.76(s,1H).13C NMR(100M,CDCl3):16.96,21.88,25.20,28.47,28.56,28.95,29.05,29.09,29.11,43.73,119.74,202.80.
Example 37 Compound (6j)
The procedure of example 28 was followed, starting from 2-vinylcyclohexanone, with a reaction time of 24 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 10:1 to 5:1, 56.4mg of product as colorless liquid, yield 68%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.32-1.46(m,2H),1.58-1.78(m,4H),1.82-1.92(m,2H),2.05-2.14(m,2H),2.28-2.42(m,5H).13C NMR(100M,CDCl3):17.17,23.08,24.81,27.77,28.60,33.97,41.90,49.75,119.50,212.26.
Example 38 Compound (6k)
The procedure of example 28 was followed, starting from cyclohexylethylene, with a reaction time of 24 h. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 30:1, 55.0mg of product as colorless liquid, yield 80%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):0.87-0.95(m,2H),1.09-1.30(m,3H),1.35-1.44(m,1H),1.55(q,J＝7.2Hz,2H),1.65-1.74(m,5H),2.35(t,J＝7.2Hz,2H).13C NMR(100M,CDCl3):14.49,25.81,26.17,32.36,32.42,36.43,119.96.
Example 39 Compound (6l)
The scheme of example 28 is adopted, allyl alcohol protected by dimethyl tertiary butyl silicon is used as a raw material, and the reaction time is 24 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 50:1, 120.7mg of colorless liquid as the product, yield 80%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):0.12(d,J＝2.0Hz,6H),0.95(s,9H),1.77-1.94(m,4H),2.43(t,J＝7.2Hz,2H),2.66(t,J＝8.4Hz,2H),3.85-3.90(m,1H),7.19-7.24(m,3H),7.30-7.34(m,2H).13C NMR(100M,CDCl3):-4.74,-4.44,12.97,17.92,25.73,31.19,32.10,38.52,69.70,119.85,125.86,128.15,128.39,141.64.IR(neat):3084,3060,3026,2952,2929,2857,2246,1603,1495,1469,1453,1362,1254,1092,993,834,774,746,698,663cm-1HRMS (EI) calculation C18H29NOSi[M]+303.2018, found 303.2010.
EXAMPLE 40 Compound (6m)
The scheme of example 1 is adopted, 2-vinyl pyridine is used as a raw material, and the reaction time is 24 hours. Silica gel column chromatography purification, eluent: petroleum ether/ethyl acetate 1:1, 60.4mg of product as colorless liquid, yield 91%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):2.84(t,J＝7.2Hz,2H),3.11(t,J＝7.2Hz,2H),7.17-7.23(m,2H),7.65(td,J＝7.6,0.8Hz,1H),8.55(d,J＝4.8Hz,1H).13C NMR(100M,CDCl3):16.37,33.09,119.27,121.98,122.90,136.55,149.36,156.97.
Example 41 Compound (1a)
At 250m LThe schlenk tube is sequentially added with NiCl2·6H2O(0.5mmol,118.8mg),Xantphos(0.6mmol,347.2mg),Zn(2mmol,130.8mg),Zn(CN)2(6mmol,704.5mg), pumping argon for three times, adding 1, 4-dioxane (50m L), p-methylstyrene (10mmol,1.18g) and water (1m L) under argon, sealing the reaction tube, placing the reaction tube in an oil bath preheated to 80 ℃ for reaction, stopping the reaction after 6 hours, cooling the reaction solution to room temperature, filtering the reaction solution with silica gel, washing with ethyl acetate, concentrating the filtrate, dissolving with 20m L ethyl acetate, and adding 3m L30% H2O2The mixture was stirred at room temperature for 10 minutes. Adding saturated Na into the reaction system2S2O3Quenching reaction, extracting with ethyl acetate, washing organic phase with water, washing with saturated NaCl, and washing with anhydrous Na2SO4Drying, filtering and concentrating, purifying by silica gel column chromatography, and eluting with an eluent: the product was 1.25g of a colorless oily liquid eluted at 30:1 petroleum ether/ethyl acetate with a yield of 86%,1h NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.62(d,J＝7.2Hz,3H),2.35(s,3H),3.86(q,J＝7.2Hz,1H),7.18(d,J＝8.0Hz,2H),7.25(d,J＝8.4Hz,2H).13C NMR(100M,CDCl3):20.98,21.44,30.80,121.73,126.52,129.71,134.05,137.78.
EXAMPLE 42 Compound (1a)
In a glove box filled with nitrogen, an 8m L sample bottle was charged with Ni (cod)2(6.9mg,0.025mmol), 9, 9-dimethyl-4, 5-bisdiphenylphosphinoxaanthracene (17.4mg,0.03mmol), 1, 4-dioxane (2.5m L) was stirred at room temperature for 10 minutes, to which Zn (CN) was further added in this order2(35.2mg,0.3mmol), and 4-methylstyrene (59.1mg,0.5 mmol). after removal of the glove box with the cap, water (50. mu. L) was added thereto, and the mixture was placed in an oil bath preheated to 80 ℃ for reaction for 4 hours, filtered through a short silica gel column, washed with ethyl acetate, concentrated, and subjected to silica gel column chromatography, with petroleum ether/ethyl acetate 100:1 to 50:1 elution to obtain 65.3mg of a colorless liquid as a product in 90% yield.1H NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.62(d,J＝7.2Hz,3H),2.35(s,3H),3.86(q,J＝7.2Hz,1H),7.18(d,J＝8.0Hz,2H),7.25(d,J＝8.4Hz,2H).13C NMR(100M,CDCl3):20.98,21.44,30.80,121.73,126.52,129.71,134.05,137.78.
EXAMPLE 43 Compound (1a)
Into a 4.0m L flask, NiCl (dppf) (0.015mmol,9.7mg), Zn (CN) were charged in this order in a nitrogen-filled glove box2(21.1mg,0.18mmol),1, 4-dioxane (1.5m L), p-methylstyrene (0.3mmol,35.5mg), then the reaction flask was taken out of the glove box with the cover closed and water (30 μ L) was added by syringe, then the reaction was stopped after 8 hours in an oil bath preheated to 80 ℃, after the reaction liquid was cooled to room temperature, the reaction was filtered on silica gel, washed with ethyl acetate, the filtrate was concentrated, and subjected to silica gel column chromatography, and petroleum ether/ethyl acetate 50:1 elution to give 37.0mg of the product as a colorless liquid with a yield of 85%.1H NMR purity was greater than 98%.1H NMR(400M,CDCl3):1.62(d,J＝7.2Hz,3H),2.35(s,3H),3.86(q,J＝7.2Hz,1H),7.18(d,J＝8.0Hz,2H),7.25(d,J＝8.4Hz,2H).13C NMR(100M,CDCl3):20.98,21.44,30.80,121.73,126.52,129.71,134.05,137.78.
Example 44 Compound (1a)
Taking the preparation of 1a as an example: the reaction was carried out under different water consumption conditions using the protocol of example 1, except for the following conditions.
a0.3mmol Scale in a 4m L Vial passing crude reaction mixture with mesitylene as internal standard1The yield was determined by H NMR.
EXAMPLE 45 Compound (1a)
Taking the preparation of 1a as an example: the reaction was carried out under different nickel catalyst conditions using the protocol of example 1, except for the following conditions.
a0.3mmol Scale in a 4m L Vial passing crude reaction mixture with mesitylene as internal standard1The yield was determined by H NMR.
Example 46 Compound (1a)
Taking the preparation of 1a as an example: the reaction was carried out under different ligand conditions using the scheme of example 1, except for the following conditions.
a0.3mmol Scale in a 4m L Vial passing crude reaction mixture with mesitylene as internal standard1The yield was determined by H NMR.
EXAMPLE 47 Compound (1a)
Taking the preparation of 1a as an example: the reaction was carried out under different solvent conditions using the protocol of example 1, except for the following conditions.
a0.3mmol Scale in a 4m L Vial passing crude reaction mixture with mesitylene as internal standard1The yield was determined by H NMR.
Example 48 Compound (1a)
Taking the preparation of 1a as an example: the protocol of example 1 was used, except that the following conditions were used, in different Zn (CN)2The reaction is carried out by using different amounts of reducing agents and under different temperature conditions.
a0.3mmol Scale in a 4m L Vial passing crude reaction mixture with mesitylene as internal standard1The yield was determined by H NMR.
Example 49 Compound (1a)
Taking the preparation of 1a as an example: the reaction was carried out using the protocol of example 1, with one-way variables, except for the following conditions.
The results are shown below: control experiment
a0.3mmol Scale in a 4m L Vial passing crude reaction mixture with mesitylene as internal standard1The yield was determined by H NMR.
COMPARATIVE EXAMPLE 1 Compound (1a)
In a glove box filled with nitrogen, NiCl was sequentially added to a 8.0m L reaction flask2·6H2O (0.025mmol,5.9mg),9, 9-dimethyl-4, 5-bis diphenylphosphinoxaanthracene (0.03mmol,17.4mg), Zn (0.1mmol,6.5mg),1, 4-dioxane (2.5m L), p-methylstyrene (0.5mmol,59.1mg) and TMSCN (99.2mg,1.0mmol), then the reaction flask was closed and taken out of the glove box and water (50. mu. L) and MeOH (32mg,1mmol) were added by syringe, then placed in an oil bath preheated to 80 ℃ for reaction, after 4 hours the reaction was stopped, after the reaction liquid was cooled to room temperature, silica gel was filtered, ether was washed, the filtrate was concentrated, homotrimethoxybenzene was added as an internal standard, nuclear magnetic core was measured, yield of product L a was 0%, the raw material remained 83%, silica gel, n-pentane was washed, and 63% of the raw material was recovered.
Claims (11)
1. A method for producing an alkylnitrile compound 1, characterized by comprising the steps of: in an organic solvent, in the presence of protective gas, under the action of a catalyst, carrying out reduction reaction on olefin shown as a formula I, a cyanation reagent and water as shown in the specification; the alkyl nitrile compound 1 is a compound II and/or a compound III;
the cyanation reagent is one or more of sodium cyanide, potassium cyanide, nickel cyanide and zinc cyanide;
the catalyst comprises a nickel compound and a phosphine ligand; the nickel compound is one or more of 0-valent nickel, monovalent nickel salt and divalent nickel salt; when the nickel-based compound comprises a divalent nickel salt, the catalyst further comprises a reducing agent;
wherein R is1Is unsubstituted or R1-1Substituted C6-14Aryl, unsubstituted or R1-2The substituted' heteroatom is selected from one or more of N, O and S, 5-20-membered heteroaryl with 1-4 heteroatom (S), unsubstituted or R1-3Substituted C1-10Alkyl, unsubstituted or R1-4Substituted C2-10Alkenyl, unsubstituted or R1-5Substituted C3-8Cycloalkyl, unsubstituted or R1-6Substituted 3-to 10-membered heterocycloalkyl in which the heteroatom is one or more selected from N, O and S and the number of heteroatoms is 1 to 4,
R1-1is-OH, -NH2、-CN、CF3Halogen, C1-10Alkyl radical, C1-10Alkoxy radical, C6-14Aryl, or, unsubstituted or R1-1-1The substituted 'heteroatom is selected from one or more of N, O, S and B, and the number of heteroatoms is 1-4';
R1-3is-OH, -CHO,
OR1-3-1、
Unsubstituted or R1-3-4Substituted C6-14Aryl, unsubstituted or R1-3-5Substituted C3-6A cycloalkyl group;
R1-2、R1-4、R1-7、R1-8、R1-9a、R1-9b、R1-9c、R1-1-1、R1-3-2、R1-3-3a、R1-3-3band R1-3-4Independently is C1-10Alkyl radical, C1-10Alkoxy, or, unsubstituted or R1-2-1Substituted C6-14An aryl group; r1-2-1is-OH, -NH2、-CN、CF3Halogen, C1-4Alkyl or C1-4An alkoxy group;
R1-5、R1-6and R1-3-5Independently is O, C1-4Alkyl or C1-4An alkoxy group;
R1-10independently is H, -OH, -NH2、-CN、CF3Halogen, C1-4Alkyl or C1-4An alkoxy group; m is 0,1, 2,3 or 4;
R1-3-1is an oxygen protecting group.
2. The method according to claim 1, wherein the reaction mixture,
the number of the 'substitution' is one or more; when there are a plurality of "substitutions", the "substitutions" may be the same or different;
and/or when R1-1When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R1-2-1When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R1-10When the halogen is fluorine, chlorine, bromine or iodine;
and/or when R1Is unsubstituted or R1-1Substituted C6-14When aryl, said C6-14Aryl is C6-10An aryl group;
and/or when R1Is unsubstituted or R1-2Substituted 5-to 20-memberedWhen the heteroaryl is a 5-to 13-membered heteroaryl, the 5-to 20-membered heteroaryl is a 5-to 13-membered heteroaryl;
and/or when R1Is unsubstituted or R1-3Substituted C1-10When alkyl, said C1-10Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl;
and/or when R1Is unsubstituted or R1-4Substituted C2-10When alkenyl, said C2-10Alkenyl is C2-6An alkenyl group;
and/or when R1Is unsubstituted or R1-5Substituted C3-8When there is a cycloalkyl group, said C3-8Cycloalkyl being C3-6A cycloalkyl group;
and/or when R1Is unsubstituted or R1-6When the heterocyclic group is a substituted 3-to 10-membered heterocyclic group, the 3-to 10-membered heterocyclic group is a 3-to 6-membered heterocyclic group;
and/or when R1-1Is C1-10When alkyl, said C1-10Alkyl is C1-4An alkyl group;
and/or when R1-1Is C1-10At alkoxy, said C1-10Alkoxy is C1-4An alkoxy group;
and/or when R1-1Is C6-14When aryl, said C6-14Aryl is C6-10An aryl group;
and/or when R1-1Is unsubstituted or R1-1-1When the heterocyclic group is a substituted 3-to 10-membered heterocyclic group, the 3-to 10-membered heterocyclic group is a 3-to 6-membered heterocyclic group;
and/or when R1-3Is unsubstituted or R1-3-4Substituted C6-14When aryl, said C6-14Aryl is C6-10An aryl group;
and/or when R1-2、R1-4、R1-7、R1-8、R1-9a、R1-9b、R1-9c、R1-1-1、R1-3-2、R1-3-3a、R1-3-3bAnd R1-3-4Independently is C1-10When alkyl, said C1-10Alkyl is C1-4An alkyl group;
and/or when R1-2、R1-4、R1-7、R1-8、R1-9a、R1-9b、R1-9c、R1-1-1、R1-3-2、R1-3-3a、R1-3-3bAnd R1-3-4Independently is C1-10At alkoxy, said C1-10Alkoxy is C1-4An alkoxy group;
and/or when R1-2、R1-4、R1-7、R1-8、R1-9a、R1-9b、R1-9c、R1-1-1、R1-3-2、R1-3-3a、R1-3-3bAnd R1-3-4Independently is unsubstituted or R1-2-1Substituted C6-14Aryl radical, said C6-14Aryl is C6-10And (4) an aryl group.
3. The method according to claim 2,
the number of the 'substitution' is 1,2, 3 or 4;
and/or when R1-1、R1-2-1And R1-10When independently halogen, said halogen is fluorine;
and/or when R1Is unsubstituted or R1-1Substituted C6-14When aryl, said C6-14Aryl is phenyl or naphthyl;
and/or when R1Is unsubstituted or R1-2When the 5-to 20-membered heteroaryl group is substituted, the 5-to 20-membered heteroaryl group is a pyridyl group, an indolyl group, a benzothienyl group or a carbazolyl group, preferably
And/or when R1Is unsubstituted or R1-3Substituted C1-10When alkyl, said C1-10Alkyl is methyl, ethyl, propyl, octyl or nonyl;
and/or when R1Is unsubstituted or R1-4Substituted C2-10When alkenyl, said C2-10Alkenyl is ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl or butadiene, preferably ethenyl;
and/or when R1Is unsubstituted or R1-5Substituted C3-8When there is a cycloalkyl group, said C3-8Cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;
and/or when R1Is unsubstituted or R1-6When the 3-to 10-membered heterocycloalkyl group is substituted, the 3-to 10-membered heterocycloalkyl group is a tetrahydrofuranyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group or morpholinyl group, preferably
And/or when R1-1Is C1-10When alkyl, said C1-10Alkyl is methyl or isobutyl;
and/or when R1-1Is C1-10At alkoxy, said C1-10Alkoxy is methoxy;
and/or when R1-1Is C6-14When aryl, said C6-14Aryl is phenyl;
and/or when R1-1Is unsubstituted or R1-1-1When the substituted 3-to 10-membered heterocycloalkyl group is a substituted 3-to 10-membered heterocycloalkyl group
And/or when R1-3Is unsubstituted or R1-3-4Substituted C6-14When aryl, said C6-14Aryl is phenyl or naphthyl;
and/or when R1-3Is unsubstituted or R1-3-5Substituted C3-6When there is a cycloalkyl group, said C3-6Cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;
and/or when R1-2、R1-4、R1-7、R1-8、R1-9a、R1-9b、R1-9c、R1-1-1、R1-3-2、R1-3-3a、R1-3-3bAnd R1-3-4Independently is C1-10When alkyl, said C1-10The alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
and/or when R1-2、R1-4、R1-7、R1-8、R1-9a、R1-9b、R1-9c、R1-1-1、R1-3-2、R1-3-3a、R1-3-3bAnd R1-3-4Independently is C1-10At alkoxy, said C1-10Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy;
and/or when R1-2、R1-4、R1-7、R1-8、R1-9a、R1-9b、R1-9c、R1-1-1、R1-3-2、R1-3-3a、R1-3-3bAnd R1-3-4Independently is unsubstituted or R1-2-1Substituted C6-14When aryl, said C6-14Aryl is phenyl;
and/or when R1-2-1、R1-5、R1-6、R1-3-5And R1-10Independently is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, propyl or isopropyl;
and/or when R1-2-1、R1-5、R1-6、R1-3-5And R1-10Independently is C1-4At alkoxy, said C1-4Alkoxy is methoxy, ethoxy, propoxy or isopropoxy;
and/or, R1-3-1Is tert-butyl diphenyl silyl or tert-butyl dimethyl silyl.
4. The method according to any one of claims 1 to 3,
when R is1Is unsubstituted or R1-1Substituted C6-14Aryl, unsubstituted or R1-2The substituted' heteroatom is selected from one or more of N, O and S, 5-20-membered heteroaryl with 1-4 heteroatom (S), unsubstituted or R1-4Substituted C2-10An alkenyl group,
Except that R1Is composed of
The compound 1 is a compound II;
and/or when R1Is unsubstituted or R1-3Substituted C1-10Alkyl, unsubstituted or R1-5Substituted C3-8Cycloalkyl, unsubstituted or R1-6Substituted 3-to 10-membered heterocycloalkyl in which the heteroatom is one or more selected from N, O and S and the number of heteroatoms is 1 to 4,
Wherein R is1-3is-CHO,
Unsubstituted or R1 -3-5Substituted C3-6Cycloalkyl, OTBS, or, unsubstituted or R14Substituted C6-14Aryl, and the compound 1 is a compound III.
5. The method according to any one of claims 1 to 3, wherein R is1Is defined as in any of the schemes below:
scheme 1: r1Is R1-1Substituted byC6-14Aryl, 5-20 membered heteroaryl having one or more unsubstituted heteroatoms selected from N, O and S and 1-4 heteroatoms, or,
Wherein the unsubstituted 5-20 membered heteroaryl is carbazolyl; r1-1Independently is C1-10Alkoxy or C6-14An aryl group;
scheme 2: r1Is unsubstituted or R1-1Substituted C6-14Aryl, unsubstituted' 5-20 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S, unsubstituted or R1-3Substituted C1-10Alkyl, unsubstituted or R1-5Substituted C3-8Cycloalkyl, unsubstituted or R1-6Substituted 3-to 10-membered heterocycloalkyl in which the heteroatom is one or more selected from N, O and S and the number of heteroatoms is 1 to 4,
Wherein the unsubstituted 5-20 membered heteroaryl is indolyl; r1-1is-NH2、C1-10Alkoxy, unsubstituted or R1-1-1The substituted 'heteroatom is selected from one or more of N, O, S and B, and the number of heteroatoms is 1-4'; r1-3is-OH, -CHO,
OR1-3-1、
R1-3-4Substituted C6-14Aryl, unsubstituted or R1-3-5Substituted C3-6A cycloalkyl group;
scheme 3: r1Is unsubstituted or R1-1Substituted C6-14Aryl or 5-20 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S as unsubstituted heteroatoms; wherein the unsubstituted 5-20 membered heteroaryl is carbazolyl; r1-1is-OH or CF3；
Scheme 4: r1Is composed of
Scheme 5: r1Is unsubstituted or R1-3Substituted C1-10An alkyl group, or,
Wherein R is1-3Is composed of
Or, unsubstituted or R1-3-4A substituted phenyl group.
6. The preparation method according to any one of claims 1 to 3, wherein the olefin represented by the formula I is selected from any one of the following structures:
or, the olefin shown in the formula I is selected from any one of the following structures:
or, the olefin shown in the formula I is selected from any one of the following structures:
7. the method of claim 1, wherein the cyanating agent is zinc cyanide;
and/or the organic solvent is one or more of an aromatic solvent, an ether solvent, a halogenated hydrocarbon solvent, a nitrile solvent, an amide solvent and a sulfoxide solvent;
and/or the protective gas is one or more of nitrogen, helium, argon and neon;
and/or the phosphine ligand is triphenylphosphine, triphenyl phosphite, tributylphosphine and tricyclohexylphosphine (PCy)3) One or more of dimethylphenylphosphine, diphenylmethylphosphine, bisdiphenylphosphinomethane, 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1, 4-bis (diphenylphosphino) butane, 1' -bis (diphenylphosphino) ferrocene, bis (2-diphenylphosphinophenyl) ether, 9-dimethyl-4, 5-bisdiphenylphosphine xanthene and 4, 5-bis (di-t-butylphosphino) -9, 9-dimethylxanthene;
and/or, in the catalyst, the nickel compound and the phosphine ligand are independent compounds, or part or all of the nickel compound and part or all of the phosphine ligand are complex compounds;
and/or the reducing agent is one or more of Zn, Mn and Al;
and/or the nickel compound and the water are independent compounds, or part or all of the nickel compound and part or all of the water form a crystalline hydrate;
and/or when the catalyst further comprises a reducing agent, the molar ratio of the olefin shown as the formula I to the reducing agent is 1: 0.01-10;
and/or the molar ratio of the olefin shown as the formula I to the nickel compound is 1: 0.01-1;
and/or the molar ratio of the nickel compound to the phosphine ligand is 1: 1-10;
and/or the mol ratio of the olefin shown in the formula I to the cyanation reagent is 1: 0.1-10;
and/or the molar concentration of the olefin shown in the formula I in the organic solvent is 0.01-1 mmol/m L;
and/or the molar ratio of the olefin shown as the formula I to the water is 1: 1-10;
and/or the temperature of the reduction reaction is 20-100 ℃.
8. The method according to claim 7, wherein the organic solvent is an ether solvent and/or a nitrile solvent;
and/or, when the organic solvent is an aromatic solvent, the aromatic solvent is one or more of benzene, toluene and xylene;
and/or, when the organic solvent is an ether solvent, the ether solvent is one or more of diethyl ether, 1, 4-dioxane and tetrahydrofuran;
and/or, when the organic solvent is a halogenated hydrocarbon solvent, the halogenated hydrocarbon solvent is one or more of dichloromethane, dichloroethane and chloroform;
and/or, when the organic solvent is a nitrile solvent, the nitrile solvent is acetonitrile;
and/or, when the organic solvent is an amide solvent, the amide solvent is N, N-dimethylformamide and/or methylphosphoramide;
and/or, when the organic solvent is a sulfoxide solvent, the sulfoxide solvent is dimethyl sulfoxide;
and/or the protective gas is nitrogen;
and/or the phosphine ligand is one or more of 1, 3-bis (diphenylphosphino) propane, 1' -bis (diphenylphosphino) ferrocene and 9, 9-dimethyl-4, 5-bis diphenylphosphine xanthene;
and/or, the 0-valent nickel is Ni (cod)2；
And/or, the monovalent nickel salt is NiCl;
and/or the divalent nickel salt is Ni (acac)2、NiCl2、NiCl2(DME)、NiBr2(DME)、NiI2And Ni (ClO)4)2One or more ofSeed growing;
and/or, in the catalyst, when part or all of the nickel compound and part or all of the phosphine ligand are complex compounds, the complex compound is one or more of a complex compound of 0-valent nickel and phosphine ligand, a complex compound of monovalent nickel salt and phosphine ligand and a complex compound of divalent nickel salt and phosphine ligand;
and/or, the reducing agent is Zn;
and/or, when part or all of the nickel compound and part or all of the water form a crystalline hydrate; the crystalline hydrate is formed by 0-valent nickel and water and/or the crystalline hydrate formed by divalent nickel salt and water;
and/or the water is deionized water;
and/or when the catalyst further comprises a reducing agent, the molar ratio of the olefin shown as the formula I to the reducing agent is 1: 0.2-1;
and/or the molar ratio of the olefin shown as the formula I to the nickel compound is 1: 0.03-0.06;
and/or the molar ratio of the nickel compound to the phosphine ligand is 1: 1.1-1.4;
and/or the mol ratio of the olefin shown in the formula I to the cyanation reagent is 1: 0.5-0.8;
and/or the molar concentration of the olefin shown in the formula I in the organic solvent is 0.1-0.4 mmol/m L;
and/or the molar ratio of the olefin shown as the formula I to the water is 1: 1-6;
and/or the temperature of the reduction reaction is 50-80 ℃;
and/or when the phosphine ligand is 1, 3-bis (diphenylphosphino) propane, adding N, N-dimethylpyridine as an additive in the reduction reaction; the mol ratio of the olefin shown in the formula I to the N, N-dimethyl pyridine is 1: 0.1-3.
9. The method according to claim 8,
in the catalyst, when part or all of the nickel compound and part or all of the phosphine ligand are complex, and the complex is complex of 0-valent nickel and phosphine ligand, the complex is Ni (PPh)3)4；
And/or, in the catalyst, when part or all of the nickel compound and part or all of the phosphine ligand are complex compounds, and the complex compound is a complex compound of monovalent nickel salt and phosphine ligand, the complex compound is NiCl (dppf);
and/or, in the catalyst, when part or all of the nickel compounds and part or all of the phosphine ligands are complexes, and the complexes are complexes of divalent nickel salts and phosphine ligands, the complexes are NiCl2(PPh3)4、NiCl2(dppf)、NiBr2(PPh3)2、NiCl2(PCy3)3、NiCl2(dppp) and NiCl2(dppe) one or more;
and/or, in the catalyst, the nickel compound and the phosphine ligand are independent compounds;
and/or, when part or all of the nickel compounds and part or all of the water form crystal hydrates, and the crystal hydrates are crystal hydrates formed by divalent nickel salts and water, the crystal hydrates are NiCl2·6H2O、NiI2·6H2O、Ni(acac)2·2H2O and Ni (ClO)4)2·6H2One or more of O.
10. The method according to claim 9,
when part or all of the nickel compounds and part or all of the water form crystal hydrates, and the crystal hydrates are crystal hydrates formed by divalent nickel salt and water, the crystal hydrates are NiCl2·6H2O and/or Ni (Cl)O4)2·6H2O；
And/or the catalyst is divalent nickel salt, phosphine ligand and Zn; the divalent nickel salt is NiCl2And/or Ni (ClO)4)2The phosphine ligand is 1, 1' -bis (diphenylphosphino) ferrocene and/or 9, 9-dimethyl-4, 5-bis-diphenylphosphine xanthene phosphine ligand.
11. An olefinic compound of the formula I-1:
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| CN114956929A (en) * | 2022-05-13 | 2022-08-30 | 华中师范大学 | Synthesis method of chiral nitrile compound |
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| CN116947695A (en) * | 2023-09-19 | 2023-10-27 | 上海如鲲新材料股份有限公司 | Preparation method and application of 1,3, 6-hexanetrinitrile |
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