CN111925356B - 手性喹啉-咪唑啉配体的合成方法及其应用 - Google Patents
手性喹啉-咪唑啉配体的合成方法及其应用 Download PDFInfo
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- CN111925356B CN111925356B CN202010824632.5A CN202010824632A CN111925356B CN 111925356 B CN111925356 B CN 111925356B CN 202010824632 A CN202010824632 A CN 202010824632A CN 111925356 B CN111925356 B CN 111925356B
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- optionally substituted
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- alkyl
- quinoline
- nickel
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- 239000003446 ligand Substances 0.000 title claims abstract description 67
- 238000001308 synthesis method Methods 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 100
- -1 amine acyl chloride Chemical class 0.000 claims abstract description 77
- 238000000034 method Methods 0.000 claims abstract description 24
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000001408 amides Chemical class 0.000 claims abstract description 8
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 150000001412 amines Chemical class 0.000 claims description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 229910052751 metal Inorganic materials 0.000 claims description 19
- 239000002184 metal Substances 0.000 claims description 19
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 14
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 13
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000003107 substituted aryl group Chemical group 0.000 claims description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 239000012320 chlorinating reagent Substances 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 150000003623 transition metal compounds Chemical class 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 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 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 239000008096 xylene Substances 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 239000012190 activator Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Substances CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 4
- 229940043279 diisopropylamine Drugs 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical group [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 229910052759 nickel Inorganic materials 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 3
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 3
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 3
- 229910052748 manganese Inorganic materials 0.000 claims description 3
- 239000011572 manganese Substances 0.000 claims description 3
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- ALDOUWLIYKWJTN-UHFFFAOYSA-N fluoro(dioxido)borane;nickel(2+) Chemical compound [Ni+2].[O-]B([O-])F ALDOUWLIYKWJTN-UHFFFAOYSA-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
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 229910052743 krypton Inorganic materials 0.000 claims description 2
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 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
- 150000002815 nickel Chemical class 0.000 claims description 2
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 claims description 2
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 claims description 2
- ZLQBNKOPBDZKDP-UHFFFAOYSA-L nickel(2+);diperchlorate Chemical compound [Ni+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O ZLQBNKOPBDZKDP-UHFFFAOYSA-L 0.000 claims description 2
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+2].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 ZBRJXVVKPBZPAN-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
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 3
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 claims 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 claims 1
- 150000001336 alkenes Chemical class 0.000 abstract description 51
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 abstract description 38
- 238000003786 synthesis reaction Methods 0.000 abstract description 26
- 238000006555 catalytic reaction Methods 0.000 abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 7
- 230000003197 catalytic effect Effects 0.000 abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 2
- 239000001301 oxygen Substances 0.000 abstract description 2
- 229910052760 oxygen Inorganic materials 0.000 abstract description 2
- 150000003141 primary amines Chemical class 0.000 abstract description 2
- QRDZFPUVLYEQTA-UHFFFAOYSA-N quinoline-8-carboxylic acid Chemical compound C1=CN=C2C(C(=O)O)=CC=CC2=C1 QRDZFPUVLYEQTA-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052723 transition metal Inorganic materials 0.000 abstract description 2
- 150000003624 transition metals Chemical class 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- 230000036632 reaction speed Effects 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 34
- 230000015572 biosynthetic process Effects 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- 150000001805 chlorine compounds Chemical class 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- 239000007858 starting material Substances 0.000 description 20
- 150000004820 halides Chemical class 0.000 description 19
- 150000003951 lactams Chemical class 0.000 description 13
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 9
- 230000035484 reaction time Effects 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- SAVNWWOBXTXNIE-CYBMUJFWSA-N N-[(2S)-1-hydroxy-3,3-dimethylbutan-2-yl]quinoline-8-carboxamide Chemical compound OC[C@H](C(C)(C)C)NC(=O)C=1C=CC=C2C=CC=NC=12 SAVNWWOBXTXNIE-CYBMUJFWSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
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- JRTIUDXYIUKIIE-KZUMESAESA-N (1z,5z)-cycloocta-1,5-diene;nickel Chemical compound [Ni].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 JRTIUDXYIUKIIE-KZUMESAESA-N 0.000 description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 3
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 3
- 239000004914 cyclooctane Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- WHGYCGOFTBFDLW-UHFFFAOYSA-L nickel(2+);diperchlorate;hexahydrate Chemical compound O.O.O.O.O.O.[Ni+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O WHGYCGOFTBFDLW-UHFFFAOYSA-L 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 2
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 150000003953 γ-lactams Chemical class 0.000 description 2
- JBULSURVMXPBNA-RXMQYKEDSA-N (2s)-2-amino-3,3-dimethylbutan-1-ol Chemical compound CC(C)(C)[C@H](N)CO JBULSURVMXPBNA-RXMQYKEDSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- PZVKSFBOPQYWGM-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole;pyridine Chemical class C1CN=CO1.C1=CC=NC=C1 PZVKSFBOPQYWGM-UHFFFAOYSA-N 0.000 description 1
- WRDWWAVNELMWAM-UHFFFAOYSA-N 4-tert-butylaniline Chemical compound CC(C)(C)C1=CC=C(N)C=C1 WRDWWAVNELMWAM-UHFFFAOYSA-N 0.000 description 1
- DWUQLWOJRVANNK-UHFFFAOYSA-N 8-(4,5-dihydroimidazol-1-yl)quinoline Chemical compound N1=CC=CC2=CC=CC(=C12)N1C=NCC1 DWUQLWOJRVANNK-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 1
- BZRRQSJJPUGBAA-UHFFFAOYSA-L cobalt(ii) bromide Chemical compound Br[Co]Br BZRRQSJJPUGBAA-UHFFFAOYSA-L 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 238000010496 migratory insertion reaction Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- CLSUSRZJUQMOHH-UHFFFAOYSA-L platinum dichloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1825—Ligands comprising condensed ring systems, e.g. acridine, carbazole
- B01J31/183—Ligands comprising condensed ring systems, e.g. acridine, carbazole with more than one complexing nitrogen atom, e.g. phenanthroline
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
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- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
- C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
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Abstract
本发明涉及一种手性喹啉‑咪唑啉配体、其合成方法及其应用。合成方法主要包括以下步骤:喹啉‑8‑甲酸与β‑氨基醇缩合得到酰胺,然后在二氯亚砜或/和五氯化磷的作用下与一级胺反应得到喹啉‑咪唑啉配体。该手性喹啉‑咪唑啉配体可用于过渡金属催化的烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应来高产率、高对映选择性地合成手性内酰胺化合物。本发明绿色环保,从廉价易得的原料出发,以简洁高效的路线合成了具有不对称催化调控潜力的手性配体,合成反应速度快,收率高,产品对水氧稳定,易储存;且配体在不对称催化领域具有重要的实际应用价值与潜力。
Description
技术领域
本发明涉及一种喹啉-咪唑啉配体的合成方法及其应用,特别是一种具有手性8-(4,5-二氢-1H-咪唑基)喹啉配体及其制备方法和其在烯烃栓系的胺酰氯与卤代物的不对称双官能团化反应方面的应用,属于有机合成技术领域。
背景技术
不对称催化是有机化学领域中一类十分重要的分支。由于在手性药物、农药及其它功能材料的发展中占据核心地位,因此,在过去几十年里不对称催化合成迅猛发展,至今仍然是化学家们最为关注的热点之一。金属不对称催化反应所涉及的领域更广,能够进行的不对称催化反应种类多,所能够合成的手性化合物的结构也多样复杂。由于有机配体可以影响金属催化剂的位阻及电子云密度,因此提高金属不对称催化反应的反应性、区域性及对映选择性的关键是发展新型高效的手性配体[Privileged Chiral Ligands andCatalysts,ed.Q.-L.Zhou,Weinheim,Wiley-VCH,2011;W.Tang and X.Zhang,Chem.Rev.,2003,103,3029;G.Desimoni,G.Faita and K.A.Chem.Rev.,2011,111,PR284]。
在手性配体发展的早期,手性有机膦配体由于在许多金属催化反应中发挥良好的协同催化活性而占据主导地位,但是仍然有许多不对称的反应利用手性膦配体是无法实现的。随后发展了手性吡啶-噁唑啉[H.Brunner,U.Obermann and P.Wimmer,J.Organomet.Chem.,1986,316,C1;H.Nishiyama,H.Sakaguchi,T.Nakamura,M.Horihata,M.Kondo and K.Itoh,Organometallics,1989,8,846;]、双噁唑啉[J.Zhou and Y.Tang,J.Am.Chem.Soc.,2002,124,9030;R.E.Lowenthal,A.Abiko and S.Masamune,TetrahedronLett.,1990,31,6005;D.A.Evans,K.A.Woerpel,M.M.Hinman and M.M.Faul,J.Am.Chem.Soc.,1991,113,726]、苯基-膦-噁唑啉[P.von Matt and A.Pfaltz,Angew.Chem.,Int.Ed.Engl.,1993,32,566]、及其他类型的手性氮配体,克服了之前大部分不对称催化反应中存在的对映选择性低效的问题。其中手性双氮配体的可修饰性强,除了氮原子与金属的螯合角及配位过渡态的环系之外,还可通过调节配体的电子和空间效应,使得配体在不同的不对称催化反应中发挥出独特催化性能。
尽管手性双氮配体在不对称金属催化剂的研究有了长足的进展,由于每一类型配体对不同反应或者同一反应不同底物的适用性都有所限制,至今仍然有许多反应的对映选择性和反应效率不能都令人满意。因此设计具有不同催化活性和手性诱导环境的手性双氮配体、拓展这类优势骨架并探究不对称催化反应中的关键诱导因素是目前亟待解决的问题。
γ-内酰胺化合物是许多生物活性分子与药物普遍存在的核心骨架,近年来许多化学工作者付诸努力,从有机合成及酶催化出发,致力发展更为高效的方法构建手性γ-内酰胺砌块。[M.Hayashi,S.Bachman,S.Hashimoto,C.C.Eichman and B.M.Stoltz,J.Am.Chem.Soc.2016,138,8997;C.Chen,S.Jin,Z.Zhang,B.Wei,H.Wang,K.Zhang,H.Lv,X.-Q.Dong and X.Zhang,J.Am.Chem.Soc.2016,138,9017;Y.Park and S.Chang,Nat.Catal.2019,2,219;K.F.Biegasiewicz,S.J.Copper,X.Gao,D.G.Oblinsky,J.H.Kim,S.E.Garfinkle,L.A.Joyce,B.A.Sandoval,G.D.Scholes and T.K.Hyster,Science 2019,364,1166.]然而,由于潜在的过度烷基化副反应以及在碱性条件下的差向异构化,从简单易得的内酰胺出发合成不对称的α-单取代的γ-内酰胺至今仍然极具挑战性,即使化学计量的手性碱也只能以较低对映选择性和收率得到手性内酰胺[J.-i.Mastuo,S.Kobayashiand K.Koga,Tetrahedron Lett.1998,39,9723]。
烯烃作为最常用的合成子之一,其多样化修饰是有机合成中的十分重要的研究。过渡金属催化烯烃的不对称双官能团化是一种十分高效的合成策略,它能在引入两个不同的官能团片段的同时实现复杂分子的构建。然而,多数分子内烯烃的环化需要依靠1,1-二取代烯烃来实现苯并杂环体系的合成[K.Wang,Z.Ding,Z.Zhou and W.Kong,J.Am.Chem.Soc.2018,140,12364;Y.Jin,C.Wang,Angew.Chem.,Int.Ed.2019,58,6722;T.Ma,Y.Chen,Y.Li,Y.Ping,W.Kong,ACS Catal.2019,9,9127]。可能由于迁移***大多是通过自由基途径,其立体选择性难以控制,因此,单取代烯烃参与的不对称双官能团化反应合成非苯并体系的手性杂环化合物仍然是目前存在的难题之一。[Y.Peng,X.-B.Xu,J.XiaoandY.-W.Wang,Chem.Commun.2014,50,472;Y.Kuang,X.Wang,D.Anthony,T.Diao,Chem.Commun.2018,54,2558.]。烯烃栓系的胺酰氯是一类合成含氮杂环十分良好的前体[A.Whyte,K.I.Burton,J.Zhang and Mark Lautens Angew.Chem.,Int.Ed.2018,57,13927;P.Fan,Y.Lan,C.Zhang and Chuan Wang,J.Am.Chem.Soc.2020,142,2180;Y.Lan,C.Wang,Commun.Chem.2020,3,45.],其合成简单,原料易得,且反应性有别于一般的烯烃栓系的烷基卤代物。因此,单取代烯烃栓系的胺酰氯的不对称的双官能化有非常大的研究空间与开发前景。
综上所述,本领域亟需能够温和高效地实现烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化的高效催化配体及手性环内酰胺的高效合成方法。
发明内容
本发明的目的在于提供一种手性喹啉-咪唑啉配体的合成方法与其在烯烃栓系的胺酰氯与卤代物间的烯烃不对称双官能团化反应方面的应用。本发明的喹啉-咪唑啉配体对水、氧均不敏感,稳定性好并且合成简单高效,在催化烯烃的不对称双官能团化反应中获得了很高的反应收率以及优秀的对映选择性,为催化烯烃的不对称双官能团化反应提供了一类型新配体产品,也为手性内酰胺的合成提供了高效、绿色且实用的合成方法。
本发明提供一种如式1所示的手性喹啉-咪唑啉配体:
其中,R1为任选取代的烷基、任选取代的环烷基、任选取代的苄基、任选取代的芳基或任选取代的杂芳基;
R2为任选取代的烷基、任选取代的环烷基、任选取代的苄基、任选取代的芳基、任选取代的杂芳基、酯基、酰胺基、硼酯基、酰基、氰基、胺基、氨基;
R3-R8各自独立地为氢、任选取代的烷基、任选取代的环烷基、任选取代的苄基、任选取代的芳基、任选取代的杂芳基、硝基、酯基、酰胺基、硼酯基、酰基、醛基、氰基、胺基、氨基、烷基-氧基、烷基-S基、卤素;
所述“任选取代”为未被取代、或被如下基团取代:烷基、烷基-氧基、烷基-S基、卤素、硝基、酯基、酰基、氰基、醛基、硼酯基、酰胺基、胺基、氨基或任选取代的苯基;所述“取代”的个数可不做限定;
用*标注的碳为S构型手性碳或R构型手性碳。
在本发明一优选实施方案中,当所述R1为任选取代的烷基时,所述烷基为C1~C10的烷基、优选地,所述烷基为C1~C6烷基,更为优选地,所述烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、或己基。
在本发明一优选实施方案中,当所述R1为任选取代环烷基时,所述环烷基为C3~C30的环烷基,优选地,所述环烷基为C3~C8的环烷基,更为优选地,所述环烷基为环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基或环辛烷基。
在本发明一优选实施方案中,当所述R1为任选取代的芳基时,所述任选取代的芳基为苯基、甲基取代的苯基、三氟甲基取代的苯基、甲氧基取代的苯基、叔丁基取代的苯基、氟取代的苯基、萘基。
在本发明一优选实施方案中,当所述R1为任选取代的杂芳基时,所述杂芳基为呋喃基、噻吩基、吲哚基或吡啶基。
在本发明一优选实施方案中,当所述R2为任选取代的烷基时,所述烷基为C1~C10的烷基、优选地,所述烷基为C1~C6烷基,更为优选地,所述烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、或己基。
在本发明一优选实施方案中,当所述R3-R8各自独立地为任选取代的烷基时,所述烷基为C1~C10的烷基、优选地,所述烷基为C1~C6烷基,更为优选地,所述烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、或己基。
在本发明一优选实施方案中,当所述R3-R8各自独立地为任选取代环烷基时,所述环烷基为C3~C30的环烷基,优选地,所述环烷基为C3~C8的环烷基,更为优选地,所述环烷基为环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基或环辛烷基。
在本发明一优选实施方案中,当所述R3-R8各自独立地为任选取代的芳基时,所述芳基为苯基。
在本发明一优选实施方案中,当所述R3-R8各自独立地为任选取代的杂芳基时,所述杂芳基为呋喃基、噻吩基、吲哚基或吡啶基。
在本发明一优选实施方案中,所述手性喹啉-咪唑啉配体为如下所示任一化合物:
用*标注的碳为S构型手性碳或R构型手性碳。
本发明还提供一种上述的配体的制备方法,包括如下步骤:在有机溶剂中,在氯化剂和碱的作用下,将如式b所示的化合物和如式d所示的化合物进行如下所示的反应,得到所述的如式1所示化合物即可,
其中,R1、R2、R3、R4、R5、R6、R7、R8和*的定义如上所定义。
在本发明中,所述的有机溶剂可为本领域该类反应常规的有机溶剂,如所述的有机溶剂包括选自甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、2-甲基四氢呋喃、二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、苯、甲苯、二甲苯、***、甲基叔丁基醚、环戊基甲基醚、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、氯化亚砜中的一种或几种;优选氯化亚砜。
在本发明中,所述的氯化剂可为本领域该类反应常规的氯化剂,如所述的氯化剂为氯化亚砜和/或五氯化磷。
在本发明中,所述的碱可为本领域该类反应常规的碱,如所述的碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢化锂、氢化钾、氢化钠、吡啶、三乙胺、三丁胺、N,N-二异丙胺、N,N-二异丙基乙基胺、2,6-二甲基吡啶、N-甲基***啉、N,N-二乙基异丙基胺、叔丁醇钠、叔丁醇钾、叔丁醇锂、甲醇钠、甲醇钾、甲醇锂;优选三乙胺。
在本发明中,所述的反应温度可为本领域该类反应常规的反应温度,如所述的第一步的反应温度为0-120℃,较为优选地,50-90℃,例如,80℃;如所述的第二步的反应温度为0-100℃,较为优选地,10-60℃,例如,室温。
在本发明中,所述的反应时间可为本领域该类反应常规的反应时间,如第一步的反应时间为1-40h,较为优选地,5-20h,例如12h;如第二步的反应时间为1-40h,较为优选地,5-20h,例如12h。
在本发明一优选实施方案中,所述的如式b所示的化合物在所述有机溶剂中的摩尔浓度为0.01-5mol/L,较为优选的,0.1-2mol/L,例如,1mol/L。
在本发明一优选实施方案中,所述的如式b所示的化合物与所述的氯化剂的摩尔比为1:1-1:100,较为优选的,1:10-1:50,例如,1:33。
在本发明一优选实施方案中,所述的如式b所示的化合物与所述的碱的摩尔比为1:1-1:30,较为优选的,1:5-1:20,例如,1:10。
在本发明一优选实施方案中,所述的如式b所示的化合物与所述的如式d所示的化合物的摩尔比为1:0.5-1:3,较为优选的,1:1-1:1.5,例如,1:1.1。
在本发明一优选实施方案中,所述的第一步反应结束后还包括减压脱溶。
在本发明一优选实施方案中,所述的第二步反应结束后还包括淬灭。所述的淬灭所用的溶液可为本领域该类反应常规的淬灭溶液,例如氢氧化钠溶液或氢氧化钾溶液。
在本发明一优选实施方案中,所述的第二步反应结束后还包括后处理步骤,所述的后处理步骤可为本领域中常规的后处理步骤,所述后处理步骤包括洗涤、干燥、层析步骤中的一步或多步。
在本发明一优选实施方案中,所述的洗涤所用溶液可为本领域常规洗涤溶液,例如饱和氯化钠溶液;所述的干燥可采用本领域常规的干燥剂,如无水硫酸钠、无水硫酸镁;所述的层析可为本领域常规柱层析,所述层析所用洗脱剂可为本领域常规洗脱剂,如石油醚、二氯甲烷、乙酸乙酯和甲醇中的一种或几种的混合物。
在本发明一优选实施方案中,还包括如下步骤,在有机溶剂中,在羰基活化剂与碱的作用下,将如式a所示的化合物和如式e所示的化合物进行如下所示的反应,得到所述的如式b所示的化合物,
其中,R1、R2、R3、R4、R5、R6、R7、R8和*的定义如上所定义。
在本发明中,所述的碱可为本领域该类反应常规的碱,如所述的碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢化锂、氢化钾、氢化钠、吡啶、三乙胺、三丁胺、N,N-二异丙胺、N,N-二异丙基乙基胺、2,6-二甲基吡啶、N-甲基***啉、N,N-二乙基异丙基胺、叔丁醇钠、叔丁醇钾、叔丁醇锂、甲醇钠、甲醇钾、甲醇锂;优选三乙胺、N,N-二异丙胺、N,N-二异丙基乙基胺、2,6-二甲基吡啶、N-甲基***啉;进一步优选N-甲基***啉。
在本发明中,所述的有机溶剂可为本领域该类反应常规的有机溶剂,如所述的有机溶剂包括选自甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、2-甲基四氢呋喃、二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、苯、甲苯、二甲苯、***、甲基叔丁基醚、环戊基甲基醚、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、氯化亚砜中的一种或几种;进一步优选二氯甲烷。
在本发明中,所述的羰基活化剂可为本领域该类反应常规的羰基活化剂,如所述的羰基活化剂为氯甲酸甲酯、氯甲酸乙酯、氯甲酸异丙酯、氯甲酸异丁酯、氯甲酸叔丁酯、羰基二咪唑、N,N’-二环己基碳二酰亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺及其盐酸盐,较为优选的,氯甲酸异丁酯。
在本发明中,所述的反应温度可为本领域该类反应常规的反应温度,如所述的反应温度为0-100℃,较为优选地,0-30℃,例如0℃、25℃。
在本发明中,所述的反应时间可为本领域该类反应常规的反应时间,如0.5-40h,例如24h。
在本发明一优选实施方案中,所述的反应结束后还包括淬灭。所述的淬灭所用的溶液可为本领域该类反应常规的淬灭溶液,例如水。
在本发明一优选实施方案中,所述的反应结束后还包括后处理步骤,所述的后处理步骤可为本领域中常规的后处理步骤,所述后处理步骤包括洗涤、干燥、层析步骤中的一步或多步。
在本发明一优选实施方案中,所述的洗涤所用溶液可为本领域常规洗涤溶液,例如饱和氯化钠溶液。所述的干燥可采用本领域常规的干燥剂,如无水硫酸钠。所述的层析可为本领域常规柱层析,所述层析所用洗脱剂可为本领域常规洗脱剂,如石油醚和乙酸乙酯的混合物。
本发明还提供一种络合物,包括上述的如式1所示的喹啉-咪唑啉配体和过渡金属化合物,所述过渡金属化合物包括氯化钴、溴化钴、氯化镍、溴化镍、碘化镍、高氯酸镍、四氟硼酸镍、六氟磷酸镍、溴化(乙二醇二甲醚)合镍、氯化(乙二醇二甲醚)合镍、双(1,5-环辛二烯)合镍、双(三苯基膦)合二氯化镍、乙酰丙酮镍及以上镍盐所对应的水合物、氯化亚铜、氯化铜、氯化钯、乙酸钯、氯化铂。
本发明还提供一种合成环内酰胺化合物的方法,包括以下步骤,在保护气体下,有机溶剂中,在上述的络合物和还原性金属单质的作用下,或者在上述喹啉-咪唑啉配体1与过渡金属金属化合物和还原性金属单质的作用下,将如式2和3所示化合物进行如下所述反应,即得到如式4所示化合物,
其中,R9、R10各自独立地为任选取代的烷基、任选取代的环烷基、任选取代的苄基、任选取代的芳基、任选取代的杂芳基、硝基、酯基、酰胺基、硼酯基、酰基、醛基、氰基、胺基、氨基、烷基-氧基、烷基-S基、卤素;卤素为氟、氯、溴、碘;
X为卤素;卤素为氟、氯、溴、碘;
所述“任选取代”为未被取代、或被如下基团取代:烷基、烷基-氧基、烷基-S基、卤素、硝基、酯基、酰基、氰基、醛基、硼酯基、酰胺基、胺基、氨基、或任选取代的苯基;所述“取代”的个数可不做限定;
用*标注的碳为S构型手性碳或R构型手性碳;
当所述络合物中的喹啉-咪唑啉配体中的*为S构型手性碳时,所述式4为如(S)-4所示的优势构型。
在本发明一优选实施方案中,当所述R9、R10各自独立地为任选取代的烷基时,所述烷基为C1~C10的烷基;优选地,所述烷基为C1~C6烷基;更为优选地,所述烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、或己基。
在本发明一优选实施方案中,当所述R9、R10各自独立地为任选取代环烷基时,所述环烷基为C3~C30的环烷基;优选地,所述环烷基为C3~C8的环烷基;更为优选地,所述环烷基为环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基或环辛烷基。
在本发明一优选实施方案中,当所述R9、R10各自独立地为任选取代的芳基时,所述任选取代的芳基为苯基、甲基取代的苯基、三氟甲基取代的苯基、甲氧基取代的苯基、叔丁基取代的苯基、氟取代的苯基、萘基。
在本发明一优选实施方案中,当所述R9、R10各自独立地为任选取代的杂芳基时,所述杂芳基为呋喃基、噻吩基、吲哚基或吡啶基。
在本发明中,所述有机溶剂可以为本领域该类反应常规的溶剂,如所述有机溶剂为甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、2-甲基四氢呋喃、二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、苯、甲苯、二甲苯、***、甲基叔丁基醚、环戊基甲基醚、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、N-甲基吡咯烷酮、乙腈、1,3-二甲基-2-咪唑啉酮中的一种或几种;优选N,N-二甲基甲酰胺。
在本发明中,所述还原性金属单质可以为本领域该类反应常规的还原性金属单质,如锌、锰。
在本发明中,所述的合成环内酰胺化合物的方法,反应物中还包括金属盐,所述金属盐可以为本领域该类反应常规的金属盐,如所述的金属盐包括氯化锂、溴化锂、碘化锂、氯化锌、氯化钠、溴化钠或碘化钠;优选溴化锂。
在本发明中,所述保护气体可以为本领域该类反应常规的保护气体,如所述的保护气体包括氮气、氩气、氦气、氖气、或氪气。
在本发明中,所述的如式2所示的化合物在所述有机溶剂中的摩尔浓度为0.01~2.0M;优选0.1-1M,例如0.2M。
在本发明中,所述的如式2所示的化合物与所述的如式3所示的化合物的摩尔比为1:5~5:1;优选1:1-1:4,例如1:3。
在本发明中,所述的如式2所示的化合物与所述络合物中配体的摩尔比为1:0.01~1:0.3;优选1:0.1-1:0.2,例如1:0.18。
在本发明中,所述的如式2所示的化合物与所述络合物中过渡金属化合物的摩尔比为1:0.01~1:0.3;优选1:0.1-1:0.2,例如1:0.15。
在本发明中,所述的如式2所示的化合物与所述金属盐的摩尔比为1:3-3:1;较为优选的,2:1-1:2,例如1:1。
在本发明中,所述反应温度可以为本领域该类反应常规的反应温度,如所述的反应温度为-20~50℃;优选-10-10℃,例如0℃。
在本发明中,所述反应时间可以为本领域该类反应常规的反应时间,如所述的反应时间为2-196h;优选20-108h,例如72h。
在本发明一优选实施方案中,所述的反应结束后还包括后处理步骤,所述的后处理步骤可为本领域中常规的后处理步骤,所述后处理步骤包括层析步骤。所述的层析可为本领域常规柱层析。
本发明的积极进步效果在于:
本发明提供的手性喹啉-咪唑啉配体,主要结构特征是具有喹啉骨架与咪唑啉基团,该分子的合成方法以喹啉甲酸为起始原料,与手性β-氨基醇缩合,随后通过氯化亚砜氯化,最后与一级胺缩合完成手性喹啉-咪唑啉配体的合成。本发明实现了目标分子的简洁、经济地大规模制备,反应条件温和、效率高;产物分子和合成方法在催化剂骨架设计以及天然药物合成方面具有重要的应用价值和潜力。
本发明提供的手性喹啉-咪唑啉配体,可作为手性配体用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应,从而合成手性环内酰胺,表现出了很高的催化活性与很高的对映选择性,具有广阔的应用前景。
总之,本发明合成方法简单,可以实现大量制备,本发明对获得手性喹啉-咪唑啉配体及其光学异构体、消旋体、催化可接受的盐,对研究和发现手性喹啉-咪唑啉配体的实际用途和应用价值具有重要意义。
具体实施方式
本发明通过下列实施例进一步举例说明,但以下实施例仅有助于进一步理解本发明,但不能限制本发明的内容。
实施例1:(S)-N-(1-羟基-3,3-二甲基-丁-2-基)喹啉-8-甲酰胺的合成:
将喹啉-8-甲酸(173.1mg,1mmol)加入到100mL的干燥反应瓶中,置换为氮气氛围,加入二氯甲烷(20mL),N-甲基***啉(0.30mL,2.7mmol),然后将反应瓶置于冰水浴中,加入氯甲酸异丁酯(0.15mL,1.15mmol),冰水浴搅拌1小时,然后加入(S)-2-氨基-3,3-二甲基-1-丁醇(175.8mg,1.5mmol),恢复至室温,搅拌24小时,TLC监测反应完全。反应液中加水(20mL)淬灭,分液,水相用二氯甲烷萃取(20mL×3),合并有机相,然后用饱和氯化钠溶液洗涤,分液,有机相用无水硫酸钠干燥,减压浓缩,柱层析(石油醚/乙酸乙酯=1:1)得到(S)-N-(1-羟基-3,3-二甲基-丁-2-基)喹啉-8-甲酰胺:白色固体,360.7mg,收率98%。
1H NMR(400MHz,CDCl3)δ1.16(d,J=6.1Hz,9H),3.70-3.80(m,2H),4.00-4.20(m,2H),7.52(dd,J=8.3,4.3Hz,1H),7.70(t,J=7.8Hz,1H),7.98(dd,J=8.1,1.6Hz,1H),8.32(dd,J=8.3,1.8Hz,1H),8.86(dd,J=7.4,1.6Hz,1H),8.93(dd,J=4.3,1.8Hz,1H),11.70(d,J=5.5Hz,1H);Anal.calcd for C16H20N2O2:C,70.55;H,7.41;N,10.29.Found:C,70.63;H,7.48;N,10.27。
实施例2:(S)-8-(4-叔丁基-1-对甲苯基-4,5-二氢-1H-咪唑2-基)喹啉的合成:
在50mL反应管中,将(S)-N-(1-羟基-3,3-二甲基-丁-2-基)喹啉-8-甲酰胺(S)-1a-b(1.5mmol)溶于氯化亚砜(1.5mL)中,90℃回流12小时,至TLC反应完全,减压脱溶,固体无需进一步后处理,直接加入至50mL反应管中,加入***(10mL)溶解,加入三乙胺(15mmol),加入对甲基苯胺(1.65mmol),室温搅拌12小时,至TLC反应完全。向反应液中加入10%氢氧化钠溶液淬灭,二氯甲烷(30mL×3)萃取,合并有机相,然后用饱和氯化钠溶液洗涤,分液,有机相用无水硫酸钠干燥,减压浓缩,柱层析(二氯甲烷/甲醇=10:1)得到(S)-8-(4-叔丁基)-1-(对甲苯基)-4,5-二氢-1H-咪唑2-基)喹啉:淡黄色固体,320mg,收率62%。1H NMR(400MHz,CDCl3):δ8.80(dd,J=4.0,2.0Hz,1H),8.06(dd,J=8.0,2.0Hz,1H),7.86–7.81(m,2H),7.52(dd,J=8.0,7.2Hz,1H),7.29(dd,J=8.0,4.0Hz,1H),6.70(d,J=8.4Hz,2H),6.56(d,J=8.4Hz,2H),4.21–4.14(m,2H),3.91-3.83(m,1H),2.08(s,3H),1.08(s,9H);13C NMR(100MHz,CDCl3):δ160.7,150.7,146.2,139.3,135.9,132.6,131.9,130.8,129.7,129.0,128.2,126.2,121.3,120.3,73.6,53.3,34.6,26.2,20.6;HRMS(ESI):[M+H]+Calcd for C23H26N3 +:344.2121;found:344.2122。
实施例3:(S)-8-(4-叔丁基-1-苯基-4,5-二氢-1H-咪唑2-基)喹啉的合成:
制备方法与实施例2相同,起始原料(S)-1a-b 0.2mmol,淡黄色固体,43.8mg,收率66%,1H NMR(400MHz,CDCl3):δ8.74(dd,J=4.0,1.6Hz,1H),8.07(dd,J=8.4,1.6Hz,1H),7.95(d,J=7.2Hz,1H),7.87(d,J=8.4,1H),7.56(t,J=7.6Hz,1H),7.29(dd,J=8.0,4.0Hz,1H),6.92(t,J=8.0Hz,2H),6.77(d,J=7.2Hz,1H),6.67(d,J=8.0Hz,1H),4.31-4.19(m,2H),3.96(dd,J=8.4,7.6Hz,1H),1.11(s,9H);13C NMR(100MHz,CDCl3):δ161.2,150.8,145.9,141.0,136.0,131.3,130.4,128.5,128.2,126.3,123.1,121.5,120.5,72.3,53.2,34.6,26.1;HRMS(ESI):[M+H]+Calcd for C22H24N3 +:330.1965;found:330.1967。
实施例4:(S)-8-(4-叔丁基-1-(对叔丁基苯基)-4,5-二氢-1H-咪唑2-基)喹啉的合成:
在10mL反应管中,将(S)-N-(1-羟基-3,3-二甲基-丁-2-基)喹啉-8-甲酰胺(S)-1a-b(0.2mmol)与氯化亚砜(0.6mmol)溶于氯仿(2mL)中回流2小时,至TLC反应完全,向体系中加入五氯化磷(0.42mmol),回流6小时,至TLC反应完全,将反应体系冷却至0℃,加入三乙胺(1.46mmol)与对叔丁基苯胺(0.44mmol)的氯仿(14.6mL)溶液,室温搅拌2小时,然后回流反应12小时,至TLC反应完全。反应液减压浓缩,向其中加入20%氢氧化钠(4mL)溶液淬灭,二氯甲烷(30mL×3)萃取,合并有机相,然后用饱和氯化钠溶液洗涤,分液,有机相用无水硫酸钠干燥,减压浓缩,柱层析(二氯甲烷/甲醇=10:1)得到淡黄色固体,55.9mg,收率73%,1H NMR(400MHz,CDCl3):δ8.76(dd,J=4.4,2.0Hz,1H),8.08(dd,J=8.0,1.6Hz,1H),7.92(dd,J=7.2,1.2Hz,1H),7.87(dd,J=8.4,1.2Hz,1H),7.55(t,J=8.0Hz,1H),7.30(dd,J=8.4,4.4Hz,1H),6.93(d,J=8.8Hz,2H),6.60(d,J=8.8Hz,2H),4.30-4.18(m,2H),3.95(dd,J=8.8,7.2Hz,1H),1.11(s,9H),1.10(s,9H);13C NMR(100MHz,CDCl3):δ161.4,150.8,146.2,146.0,138.1,136.0,131.3,130.5,128.3,126.2,125.4,121.5,120.1,71.8,53.3,34.6,34.2,31.3,26.0;HRMS(ESI):[M+H]+Calcd for C26H32N3 +:386.2591;found:386.2584。
实施例5:(S)-8-(4-叔丁基-1-(对氟苯基)-4,5-二氢-1H-咪唑2-基)喹啉的合成:
制备方法与实施例2相同,起始原料(S)-1a-b 0.2mmol,淡黄色固体,41.6mg,收率60%,1H NMR(400MHz,DMSO-d6):δ8.76(d,J=2.4Hz,1H),8.37(dd,J=8.4,1.6Hz,1H),8.09(dd,J=8.0,0.8Hz,1H),7.85(d,J=6.8Hz,1H),7.66(dd,J=8.0,7.2Hz,1H),7.49(dd,J=8.4,4.4Hz,1H),4.09-3.92(m,3H),1.01(s,9H);HRMS(ESI):[M+H]+Calcd forC22H23N3F+:348.1871;found:348.1861。
实施例6:(S)-8-(4-叔丁基-1-(对甲氧基苯基)-4,5-二氢-1H-咪唑2-基)喹啉的合成:
制备方法与实施例4相同,起始原料(S)-1a-b 0.2mmol,白色固体,30.0mg,收率42%,1H NMR(400MHz,CDCl3):δ8.80(dd,J=4.0,1.6Hz,1H),8.05(dd,J=8.4,1.6Hz,1H),7.88(dd,J=7.2,1.6,Hz,1H),7.81(dd,J=8.4,1.6Hz,1H),7.52(dd,J=8.0,7.2Hz,1H),7.30(dd,J=8.4,4.4Hz,1H),6.71(d,J=8.8Hz,2H),6.46(d,J=9.2Hz,2H),4.23-4.16(m,2H),3.89-3.84(m,1H),3.59(s,9H),1.09(s,9H);13C NMR(100MHz,CDCl3):δ161.9,155.9,150.7,146.0,136.0,134.9,131.3,131.1,130.0,128.2,126.1,123.4,121.4,113.7,73.0,55.4,54.3,34.6,26.1;HRMS(ESI):[M+H]+Calcd for C23H26N3O+:360.2070;found:360.2066。
实施例7:(S)-8-(4-叔丁基-1-(对三氟甲基苯基)-4,5-二氢-1H-咪唑2-基)喹啉的合成:
制备方法与实施例4相同,起始原料(S)-1a-b 0.2mmol,白色固体,54.6mg,收率69%,1H NMR(400MHz,CDCl3):δ8.72(dd,J=4.0,1.6Hz,1H),8.10(dd,J=8.4,1.6Hz,1H),7.90(d,J=7.6Hz,1H),7.59(t,J=7.6Hz,1H),7.31(dd,J=8.4,4.4Hz,1H),7.11(d,J=8.4,1H),6.58(d,J=8.4Hz,2H),4.19-4.15(m,2H),3.97-3.93(m,1H),1.08(s,9H);13C NMR(100MHz,CDCl3):δ159.3,150.9,146.0,144.2,136.0,132.2,130.7,130.2,128.4,126.4,125.6(q,JC-F=3.7Hz),122.9(q,JC-F=33.3Hz),121.7,117.7,73.5,52.2,34.5,26.1;19FNMR(376MHz,CDCl3):-61.8;HRMS(ESI):[M+H]+Calcd forC23H23N3F3 +:398.1839;found:398.1835。
实施例8:(S)-8-(4-叔丁基-1-(3,5-二(三氟甲基)苯基)-4,5-二氢-1H-咪唑2-基)喹啉的合成:
制备方法与实施例4相同,起始原料(S)-1a-b 0.2mmol,白色固体,39.2mg,收率42%,1H NMR(400MHz,CDCl3):δ8.62(dd,J=4.0,1.6Hz,1H),8.10(dd,J=8.4,1.6Hz,1H),7.97(dd,J=7.2,1.6Hz,1H),7.93(dd,J=8.4,1.6Hz,1H),7.62(dd,J=8.0,7.2Hz,1H),7.28(dd,J=8.4,4.0Hz 1H),7.11(s,1H),6.85(s,2H),4.23-4.19(m,2H),3.94-3.91(m,1H),1.11(s,9H);13C NMR(100MHz,CDCl3):δ159.0,150.7,145.6,142.4,135.9,131.4(q,JC-F=32.8Hz),131.3,130.9,130.5,128.3,126.4,122.9(q,JC-F=271.2Hz),121.6,117.3,113.9(q,JC-F=3.6Hz),73.8,51.7,34.4,26.1;19F NMR(376MHz,CDCl3):-63.5;HRMS(ESI):[M+H]+Calcd for C24H22N3F6 +:466.1712;found:466.1722。
实施例9:(S)-8-(4-叔丁基-1-(2,4,6-三甲基苯基)-4,5-二氢-1H-咪唑2-基)喹啉的合成:
制备方法与实施例2相同,起始原料(S)-1a-b 0.5mmol,白色固体,160.2mg,收率86%,1H NMR(400MHz,CDCl3):δ8.82(dd,J=4.0,1.2Hz,1H),7.96(d,J=8.0Hz,1H),7.90(d,J=7.6Hz,1H),7.70(d,J=8.4Hz,1H),7.42(t,J=8.0Hz,1H),7.28-7.25(m,1H),6.60(s,1H),6.55(s,1H),4.31(t,J=10.8Hz,1H),3.89-3.84(m,1H),3.71(t,J=9.6Hz,1H),2.41(s,3H),2.25(s,3H),2.03(s,3H),1.12(s,9H);13C NMR(100MHz,CDCl3):δ163.9,149.9,146.0,137.5,136.7,136.5,135.8,135.3,131.1,130.0,129.1,129.1,127.9,125.6,121.2,73.8,53.0,34.6,26.4,20.8,18.7,18.6.HRMS(ESI):[M+H]+Calcd forC25H30N3 +:372.2434;found:372.2430。
实施例10:(S)-8-(4-叔丁基-1-(金刚烷-1-基)-4,5-二氢-1H-咪唑2-基)喹啉的合成:
制备方法与实施例2相同,起始原料(S)-1a-b 0.2mmol,白色固体,42.6mg,收率55%,1H NMR(400MHz,CDCl3)δ9.00(dd,J=4.0,1.6Hz,1H),8.11(dd,J=8.4,2.0Hz,1H),7.82(dd,J=8.0,1.6Hz,1H),7.66(dd,J=7.2,1.6Hz,1H),7.53(d,J=8.0Hz,1H),7.38(dd,J=8.4,4.4Hz,1H),3.98–3.68(m,2H),3.51(t,J=9.6Hz,1H),1.91–1.22(m,15H),1.00(s,9H);HRMS(ESI):[M+H]+Calcd for C26H34N3 +:388.2747;found:388.2747。
实施例11:(S)-8-(4-叔丁基-1-环己基-4,5-二氢-1H-咪唑2-基)喹啉的合成:
制备方法与实施例4相同,起始原料(S)-1a-b 0.2mmol,白色固体,24.1mg,收率36%,1H NMR(400MHz,CDCl3):δ8.94(dd,J=4.4,1.6Hz,1H),8.16(dd,J=8.0,1.6Hz,1H),7.88(dd,J=8.4,1.2Hz,1H),7.81(dd,J=7.2,1.2Hz,1H),7.57(dd,J=8.0,7.6Hz,1H),7.40(dd,J=8.0,4.0Hz,1H),4.02(dd,J=11.2,0.8Hz,1H),3.65(dd,J=11.2,9.6Hz,1H),3.42(t,J=9.2Hz,1H),2.80-2.72(m,1H),1.88-1.85(m,1H),1.65-1.39(m,7H),1.01(s,9H),0.98-0.76(m,2H);13C NMR(100MHz,CDCl3):δ164.0,150.9,146.3,136.2,131.0,129.7,128.2,126.3,121.5,72.7,55.0,45.4,34.8,31.5,30.4,26.1,25.7,25.5.HRMS(ESI):[M+H]+Calcd for C22H30N3 +:336.2434;found:336.2432。
实施例12:(S)-8-(4-叔丁基-1-对甲苯基-4,5-二氢-1H-咪唑2-基)-3-(吡啶-2-基)喹啉的合成:
制备方法与实施例2相同,起始原料(S)-1k-b 0.2mmol,白色固体,53.0mg,收率63%,1H NMR(400MHz,CDCl3):δ9.40(d,J=2.0Hz,1H),8.75-8.73(m,1H),8.71(d,J=2.0Hz,1H),7.95(d,J=8.4,1.2Hz,1H),7.90(d,J=6.8Hz,1H),7.85-7.79(m,2H),7.57(dd,J=8.0,7.2Hz,1H),6.72(d,J=8.0Hz,2H),6.61(d,J=8.4Hz,2H),4.26-4.17(m,2H),3.95-3.89(m,1H),2.07(s,3H),1.10(s,9H)。
实施例13:(S)-8-(4-叔丁基-1-对甲苯基-4,5-二氢-1H-咪唑2-基)-3-氰基喹啉的合成:
制备方法与实施例2相同,起始原料(S)-1l-b 0.2mmol,白色固体,45.0mg,收率61%,1H NMR(400MHz,DMSO-d6)δ9.10-9.04(m,2H),8.18(d,J=8.0Hz,1H),8.02-8.00(m,1H),7.81(t,J=7.6Hz,1H),6.72(d,J=8.0Hz,2H),6.50(d,J=8.0Hz,2H),4.05–3.87(m,3H),2.01(s,3H),0.99(s,9H)。
实施例14:(S)-8-(4-新戊基-1-(对甲苯基)-4,5-二氢-1H-咪唑-2-基)喹啉的合成:
制备方法与实施例2相同,起始原料(S)-1m-b 1.0mmol,白色固体,261.6mg,收率73%,1H NMR(400MHz,CDCl3):δ8.72(d,J=2.8Hz,1H),8.01(dd,J=8.0,1.2Hz,1H),7.78(d,J=8.4Hz,2H),7.47(d,J=7.6Hz,1H),7.24(q,d=4.0Hz,1H),6.65(d,J=8.4Hz,2H),6.49(d,J=8.4Hz,2H),4.44-4.36(m,1H),4.24(t,J=9.2Hz,1H),3.78(t,J=9.2Hz,1H),2.11(dd,J=14.0,2.8Hz,1H),2.02(s,3H),1.61(dd,J=13.6,8.8Hz,1H),0.968(s,9H)。
实施例15:(S)-8-(4-苄基-1-(对甲苯基)-4,5-二氢-1H-咪唑-2-基)喹啉的合成:
制备方法与实施例2相同,起始原料(S)-1n-b 1.0mmol,白色固体,151mg,收率40%,1H NMR(400MHz,CDCl3):δ8.74(dd,J=4.0,1.6Hz,1H),8.02(dd,J=8.4,2.0Hz,1H),7.78(dd,J=8.4,1.6Hz,1H),7.73(dd,J=6.8,0.8Hz,1H),7.46(dd,J=8.0,7.2Hz,1H),7.32-7.23(m,5H),7.18-7.16(m,1H),6.61(d,J=8.0Hz,2H),6.38(d,J=8.4Hz,2H),4.73-4.67(m,1H),4.08(t,J=10.0Hz,1H),3.84(dd,J=9.2,7.6Hz,1H),3.31(dd,J=14.0,4.4Hz,1H),2.96(dd,J=13.6,8.4Hz,1H),2.0(s,3H)。
实施例16:(S)-8-(4-(叔丁基)-1-(萘-2-基)-4,5-二氢-1H-咪唑-2-基)喹啉的合成:
制备方法与实施例2相同,起始原料(S)-1a-b 0.5mmol,白色固体,80mg,收率42%,1HNMR(400MHz,CDCl3):δ8.63(dd,J=4.0,1.6Hz,1H),8.00-7.95(m,2H),7.82(dd,J=8.4,1.2Hz,1H),7.56-7.64(m,2H),7.4(d,J=8.4Hz,1H),7.25(dd,J=6.8,1.2Hz,2H),7.17(d,J=4.4Hz,2H),7.11(d,J=1.6Hz,1H),6.70(dd,J=8.8,2.0Hz,1H),4.34(t,J=10.0Hz,1H),4.21(dd,J=10.8,7.6Hz,1H),4.04(dt,J=14.4,7.2Hz,1H),1.08(s,9H);13CNMR(101MHz,CDCl3)δ150.9,145.9,136.0,133.6,131.5,130.8,130.0,128.3,128.2,127.5,127.2,126.5,126.3,124.8,121.7,120.6,77.4,53.6,34.7,26.1。
实施例17:(S)-8-(4-(叔丁基)-1-(3,5-二叔丁基苯基)-4,5-二氢-1H-咪唑-2-基)喹啉
制备方法与实施例2相同,起始原料(S)-1a-b 0.2mmol,白色固体,43mg,收率49%,1HNMR(400MHz,CDCl3):δ8.58(d,J=2.8Hz,1H),8.06(s,1H),7.98(dd,J=8.0,1.6Hz,1H),7.83(d,J=8.4Hz,1H),7.55(t,J=8.0Hz,1H),7.23-7.19(m,1H),6.83(s,1H),6.53(s,2H),4.40(s,1H),43.1-4.32(m,1H),4.04(s,1H),1.12(s,9H),0.92(s,18H)。
实施例18:(S)-8-(1-([1,1':3',1”-三联苯]-5'-基)-4-(叔丁基)-4,5-二氢-1H-咪唑-2-基)喹啉
制备方法与实施例2相同,起始原料(S)-1a-b 0.2mmol,白色固体,77mg,收率80%,1HNMR(400MHz,CDCl3):δ8.72(dd,J=4.4,1.6Hz,1H),8.08(dd,J=8.0,1.6Hz,1H),7.97-7.86(m,2H),7.57(t,J=7.2Hz,1H),7.23(m,7H),7.13(s,1H),7.06-7.01(m,4H),6.80(s,2H),4.30(t,J=9.6Hz,1H),4.23-4.15(m,1H),4.00(t,J=8.0Hz,1H),1.07(s,9H)。
实施例19:(S)-8-(4-异丙基-1-(对甲苯基)-4,5-二氢-1H-咪唑-2-基)喹啉
制备方法与实施例2相同,起始原料(S)-1r-b 0.5mmol,白色固体,150mg,收率91%,1H NMR(400MHz,CDCl3):δ8.74(dd,J=4.4,2.0Hz,1H),8.01(dd,J=8.4,1.6Hz,1H),7.81-7.74(m,2H),7.46(dd,J=8.0,7.2Hz,1H),7.24(dd,J=8.4,4.0Hz,1H),6.64(d,J=8.4Hz,2H),6.49(d,J=8.8Hz,2H),4.24-4.00(m.2H),3.80(t,J=8.8Hz,1H),2.08-1.95(m,3H),1.16(d,J=7.6Hz,1H),1.06(d,J=6.8Hz,3H),1.01(d,J=6.8Hz,3H);13C NMR(101MHz,CDCl3):δ160.8,157.3,150.7,146.0,139.0,135.8,132.0,130.8,129.9,128.9,126.1,121.3,120.2,77.2,46.0,33.2,20.6,19.0,18.0。
实施例20:(S)-8-(4-(叔丁基)-1-(对甲苯基)-4,5-二氢-1H-咪唑-2-基)-6-甲氧基喹啉
制备方法与实施例2相同,起始原料(S)-1s-b 0.2mmol,白色固体,57.7mg,收率77%,1H NMR(400MHz,CDCl3):δ8.57(dd,J=4.4,1.6Hz,1H),7.88(dd,J=8.4,2.0Hz,1H),7.47(d,J=2.8Hz,1H),7.19-7.14(m,1H),7.02(d,J=2.8Hz,1H),6.66(d,J=8.4Hz,2H),6.53(d,J=8.4Hz,2H),4.15-4.04(m,1H),3.85(s,3H),3.79(t,J=6.0Hz,1H),2.03(s,3H),1.00(s,9H);13C NMR(101MHz,CDCl3):δ160.4,157.1,148.3,142.4,139.1,134.7,129.4,129.1,123.5,121.6,120.5,107.3,77.4,55.8,53.5,46.0,34.6,26.2,20.7,9.6。
实施例21:8-((S)-4-(金刚烷-1-基)-1-对甲苯基-4,5-二氢-1H-咪唑-2-基)喹啉
制备方法与实施例2相同,起始原料(S)-1t-b 0.26mmol,白色固体,104mg,收率95%,1H NMR(400MHz,CDCl3)δ8.76(dd,J=4.4,1.6Hz,1H),8.07(dd,J=8.4,1.6Hz,1H),7.96(dd,J=7.2,0.8Hz,1H),7.86(dd,J=7.2,0.8Hz,1H),7.55(t,J=7.6Hz,1H),7.30(dd,J=8.4,4.0Hz,1H),6.74(d,J=8.4Hz,2H),6.62(d,J=8.4Hz,2H),4.23-4.16(m,1H),4.07-4.00(m,2H),2.09(s,3H),2.05(s,3H),1.83(d,J=12.4Hz,3H),1.71(m,9H);13C NMR(101MHz,CDCl3)δ161.71,150.81,145.77,138.15,136.00,133.48,131.53,130.67,129.20,128.20,126.19,121.58,121.18,71.49,52.22,38.37,37.28,36.36,28.39,20.75。
实施例22-59:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应的应用。
在手套箱中称取配体(S)-1a(0.036mmol)、双(1,5-环辛二烯)合镍(0.030mmol)、溴化锂(0.2mmol)、锰(0.8mmol)于装有强力搅拌子的干燥洁净的10mL反应管中,加入1mLN,N-二甲基甲酰胺,烯烃栓系的胺酰氯(0.2mmol)与卤代烃(0.6mmol),密封后取出,于0℃下搅拌48小时,反应液用水淬灭,经硅藻土过滤,乙酸乙酯洗涤滤饼之后,水洗3次,乙酸乙酯反萃2次,分液,合并有机相,旋转蒸发仪脱除溶剂后得粗产品,用薄层层析或核磁共振分析反应的转化率和收率,高效液相色谱分析产物的光学纯度,所得手性环内酰胺实验结果见表1。
表1.烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应生成手性环内酰胺。
实施例60:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应的兼容性尝试。
在手套箱中称取配体(S)-1a(0.036mmol)、六水合高氯酸镍(0.030mmol)、溴化锂(0.2mmol)、锰(0.8mmol)于装有强力搅拌子的干燥洁净的10mL反应管中,加入1mL N,N-二甲基甲酰胺,烯烃栓系的胺酰氯(0.2mmol)与卤代烃(0.6mmol),密封后取出,于0℃下搅拌36小时,反应液用水淬灭,经硅藻土过滤,乙酸乙酯洗涤滤饼之后,水洗3次,乙酸乙酯反萃2次,分液,合并有机相,旋转蒸发仪脱除溶剂后得粗产品,用薄层层析或核磁共振分析反应的转化率和收率,高效液相色谱分析产物的光学纯度,以75%收率、95%ee得手性环内酰胺产物。
实施例61:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应对温度的兼容性尝试。
反应条件与后处理步骤除改变为10℃下反应以外,其余同实施例60。以57%收率、93%ee得手性环内酰胺产物。
实施例62:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应对金属盐的兼容性尝试。
反应条件与后处理步骤除相同物质的量的碘化锂代替溴化锂以外,其余同实施例60。以35%收率、94%ee得手性环内酰胺产物。
实施例63:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应对金属盐的兼容性尝试。
反应条件与后处理步骤除相同物质的量的碘化钠代替溴化锂以外,其余同实施例60。以34%收率、94%ee得手性环内酰胺产物。
实施例64:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应对金属盐的兼容性尝试。
反应条件与后处理步骤除相同物质的量的溴化钠代替溴化锂以外,其余同实施例60。以43%收率、93%ee得手性环内酰胺产物。
实施例65:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应对溶剂的兼容性尝试。
反应条件与后处理步骤除相同体积的N-甲基吡咯烷酮代替N,N-二甲基甲酰胺以外,其余同实施例60。以55%收率、91%ee得手性环内酰胺产物。
实施例66:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应对溶剂的兼容性尝试。
反应条件与后处理步骤除相同体积的N,N-二甲基乙酰胺代替N,N-二甲基甲酰胺以外,其余同实施例60。以38%收率、94%ee得手性环内酰胺产物。
实施例67:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应对溶剂的兼容性尝试。
反应条件与后处理步骤除相同体积的1,3-二甲基-2-咪唑啉酮代替N,N-二甲基甲酰胺以外,其余同实施例60。以24%收率、94%ee得手性环内酰胺产物。
实施例68:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应对溶剂的兼容性尝试。
反应条件与后处理步骤除相同体积的乙腈代替N,N-二甲基甲酰胺以外,其余同实施例60。以32%收率、79%ee得手性环内酰胺产物。
实施例69:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应对反应物浓度的兼容性尝试。
反应条件与后处理步骤除使用4mL N,N-二甲基甲酰胺以外,其余同实施例60。以66%收率、94%ee得手性环内酰胺产物。
实施例70:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应对镍催化剂的兼容性尝试。
反应条件与后处理步骤除相同物质的量的溴化(乙二醇二甲醚)合镍代替六水合高氯酸镍以外,其余同实施例60。以43%收率、77%ee得手性环内酰胺产物。
实施例71:喹啉-咪唑啉配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应对镍催化剂的兼容性尝试。
反应条件与后处理步骤除相同物质的量的双(1,5-环辛二烯)合镍代替六水合高氯酸镍以外,其余同实施例60。以86%收率、94%ee得手性环内酰胺产物。
对比例1:喹啉-咪唑啉类似配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应与喹啉-咪唑啉配体的对比。
反应条件与后处理步骤除相同物质的量的(S)-L1代替(S)-1a以外,其余同实施例65。以33%收率、37%ee得手性环内酰胺产物。
对比例2:喹啉-咪唑啉类似配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应与喹啉-咪唑啉配体的对比。
反应条件与后处理步骤除相同物质的量的(S,S)-L2代替(S)-1a以外,其余同实施例65。以12%收率、11%ee得手性环内酰胺产物。
对比例3:喹啉-咪唑啉类似配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应与喹啉-咪唑啉配体的对比。
反应条件与后处理步骤除相同物质的量的(S)-L3代替(S)-1a以外,其余同实施例65。未能得手性环内酰胺产物。
对比例4:喹啉-咪唑啉类似配体应用于烯烃栓系的胺酰氯与卤代物的烯烃不对称双官能团化反应与喹啉-咪唑啉配体的对比。
反应条件与后处理步骤除所有反应物、溶剂量减半、相同物质的量的(S)-L4代替(S)-1a以外,其余同实施例22-59。以68%收率、54%ee得手性环内酰胺产物。
Claims (11)
1.一种如式1所示的喹啉-咪唑啉配体:
其中,R1为苯基、甲基取代的苯基、三氟甲基取代的苯基、甲氧基取代的苯基、叔丁基取代的苯基、氟取代的苯基、萘基或任选取代的杂芳基;当所述R1为任选取代的杂芳基时,所述杂芳基为呋喃基、噻吩基、吲哚基或吡啶基;
R2为苄基或C1~C10的烷基;
R3-R8各自独立地为氢、任选取代的烷基、任选取代的环烷基、氰基;
当所述R3-R8各自独立地为任选取代的烷基时,所述烷基为C1~C10的烷基;当所述R3-R8各自独立地为任选取代环烷基时,所述环烷基为C3~C30的环烷基;
所述“任选取代”为未被取代、或被如下基团取代:卤素、硝基、氰基、醛基或氨基;所述“取代”的个数可不做限定;
用*标注的碳为S构型手性碳或R构型手性碳。
4.根据权利要求3所述的制备方法,其特征在于,
所述的有机溶剂包括选自甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、2-甲基四氢呋喃、二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、苯、甲苯、二甲苯、***、甲基叔丁基醚、环戊基甲基醚、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜中的一种或几种;
和/或,所述的氯化剂为氯化亚砜和/或五氯化磷;
和/或,所述的碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢化锂、氢化钾、氢化钠、吡啶、三乙胺、三丁胺、N,N-二异丙胺、N,N-二异丙基乙基胺、2,6-二甲基吡啶、N-甲基***啉、N,N-二乙基异丙基胺、叔丁醇钠、叔丁醇钾、叔丁醇锂、甲醇钠、甲醇钾、甲醇锂;
和/或,所述的第一步的反应温度为0-120℃;
和/或,所述的第二步的反应温度为0-100℃;
和/或,所述的如式b所示的化合物在所述有机溶剂中的摩尔浓度为0.01-5mol/L;
和/或,所述的如式b所示的化合物与所述的氯化剂的摩尔比为1:1-1:100;
和/或,所述的如式b所示的化合物与所述的碱的摩尔比为1:1-1:30;
和/或,所述的如式b所示的化合物与所述的如式d所示的化合物的摩尔比为1:0.5-1:3。
6.一种络合物,其特征在于,包括如权利要求1-2任一项所述的喹啉-咪唑啉配体和过渡金属化合物,所述过渡金属化合物为氯化镍、溴化镍、碘化镍、高氯酸镍、四氟硼酸镍、六氟磷酸镍、溴化(乙二醇二甲醚)合镍、氯化(乙二醇二甲醚)合镍、双(1,4-环辛二烯)合镍、双(三苯基膦)合二氯化镍、乙酰丙酮镍及以上镍盐所对应的水合物。
7.一种合成环内酰胺化合物的方法,其特征在于,包括以下步骤,在保护气体下,有机溶剂中,在权利要求6所述的络合物和还原性金属单质锌或锰的作用下,将如式2和3所示化合物进行如下所述反应,即得到如式4所示化合物,
其中,R9、R10各自独立地为任选取代的烷基、任选取代的环烷基、任选取代的苄基、任选取代的芳基、任选取代的杂芳基、硝基、酯基、酰胺基、硼酯基、酰基、醛基、氰基、胺基、氨基、烷基-氧基、烷基-S基、卤素;
X为卤素;
所述卤素为碘;
所述“任选取代”为未被取代、或被如下基团取代:烷基、烷基-氧基、烷基-S基、卤素、硝基、酯基、酰基、氰基、醛基、硼酯基、酰胺基、胺基、氨基、或任选取代的苯基;所述“取代”的个数可不做限定;
用*标注的碳为S构型手性碳或R构型手性碳;
当所述络合物中的喹啉-咪唑啉配体中的*为S构型手性碳时,所述式4为如4a所示的优势构型,
8.根据权利要求7所述的方法,其特征在于,当所述R9、R10各自独立地为任选取代的烷基时,所述烷基为C1~C10的烷基;当所述R9、R10各自独立地为任选取代环烷基时,所述环烷基为C3~C30的环烷基;当所述R9、R10各自独立地为任选取代的芳基时,所述任选取代的芳基为苯基、甲基取代的苯基、三氟甲基取代的苯基、甲氧基取代的苯基、叔丁基取代的苯基、氟取代的苯基、萘基;当所述R9、R10各自独立地为任选取代的杂芳基时,所述杂芳基为呋喃基、噻吩基、吲哚基或吡啶基。
9.根据权利要求7所述的方法,其特征在于,当所述R9、R10各自独立地为任选取代的烷基时,所述烷基为C1~C6烷基;当所述R9、R10各自独立地为任选取代环烷基时,所述环烷基为C3~C8的环烷基。
10.根据权利要求7所述的方法,其特征在于,当所述R9、R10各自独立地为任选取代的烷基时,所述烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、或己基;当所述R9、R10各自独立地为任选取代环烷基时,所述环烷基为环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基或环辛烷基。
11.根据权利要求7所述的方法,其特征在于,所述有机溶剂为甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、2-甲基四氢呋喃、二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、苯、甲苯、二甲苯、***、甲基叔丁基醚、环戊基甲基醚、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、N-甲基吡咯烷酮、乙腈、1,3-二甲基-2-咪唑啉酮中的一种或几种;
和/或,所述的合成环内酰胺化合物的方法,反应物中还包括金属盐,所述的金属盐为氯化锂、溴化锂、碘化锂、氯化锌、氯化钠、溴化钠或碘化钠;
和/或,所述的保护气体包括氮气、氩气、氦气、氖气、或氪气;
和/或,所述的如式2所示的化合物在所述有机溶剂中的摩尔浓度为0.01~2.0M;
和/或,所述的如式2所示的化合物与所述的如式3所示的化合物的摩尔比为1:5~5:1;
和/或,所述的如式2所示的化合物与所述络合物中配体的摩尔比为1:0.05~1:0.3;
和/或,所述的如式2所示的化合物与所述络合物中过渡金属化合物的摩尔比为1:0.01~1:0.3;
和/或,所述的如式b所示的化合物与所述金属盐的摩尔比为1:0.01~1:0.3;
和/或,所述的反应温度为-20~50℃。
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