CN108456172A - A kind of chiral aza ring carbene precursor compound and its preparation method and application with benzimidazole skeleton - Google Patents
A kind of chiral aza ring carbene precursor compound and its preparation method and application with benzimidazole skeleton Download PDFInfo
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- CN108456172A CN108456172A CN201810361990.XA CN201810361990A CN108456172A CN 108456172 A CN108456172 A CN 108456172A CN 201810361990 A CN201810361990 A CN 201810361990A CN 108456172 A CN108456172 A CN 108456172A
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- compound
- reaction
- carbene precursor
- preparation
- chiral
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 98
- 238000002360 preparation method Methods 0.000 title claims abstract description 56
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 239000002243 precursor Substances 0.000 title claims abstract description 35
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- 229910052751 metal Inorganic materials 0.000 claims abstract description 8
- 239000002184 metal Substances 0.000 claims abstract description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 20
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000007795 chemical reaction product Substances 0.000 claims description 14
- -1 methoxybenzoyl Chemical group 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- 229910052763 palladium Inorganic materials 0.000 claims description 11
- 239000000010 aprotic solvent Substances 0.000 claims description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- DBOLXXRVIFGDTI-UHFFFAOYSA-N 4-benzylpyridine Chemical class C=1C=NC=CC=1CC1=CC=CC=C1 DBOLXXRVIFGDTI-UHFFFAOYSA-N 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 8
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical class BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 claims description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 7
- 239000000758 substrate Substances 0.000 claims description 7
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000000126 substance Substances 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
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 150000004982 aromatic amines Chemical class 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 150000001263 acyl chlorides Chemical class 0.000 claims description 3
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 claims description 2
- 125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 2
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 241000370738 Chlorion Species 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000001414 amino alcohols Chemical class 0.000 claims description 2
- 229940006460 bromide ion Drugs 0.000 claims description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical class BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 150000004985 diamines Chemical class 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 claims description 2
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- QABCGOSYZHCPGN-UHFFFAOYSA-N chloro(dimethyl)silicon Chemical compound C[Si](C)Cl QABCGOSYZHCPGN-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 239000003446 ligand Substances 0.000 abstract description 15
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 abstract description 12
- 238000006555 catalytic reaction Methods 0.000 abstract description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 3
- 239000001301 oxygen Substances 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- 230000009257 reactivity Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 42
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 8
- 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 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 0 *C[C@](c1ccccc1)NC* Chemical compound *C[C@](c1ccccc1)NC* 0.000 description 5
- 240000001414 Eucalyptus viminalis Species 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 235000015110 jellies Nutrition 0.000 description 4
- 239000008274 jelly Substances 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- LKZVJKCSPGCLCH-UHFFFAOYSA-N 4,5-dihydro-1h-imidazole;quinoline Chemical class C1CN=CN1.N1=CC=CC2=CC=CC=C21 LKZVJKCSPGCLCH-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 150000004696 coordination complex Chemical class 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 150000002561 ketenes Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- UEVKWTASYVIROP-UHFFFAOYSA-N 1-bromo-2-butylbenzene Chemical group CCCCC1=CC=CC=C1Br UEVKWTASYVIROP-UHFFFAOYSA-N 0.000 description 1
- 150000005004 2-naphthylamines Chemical class 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical compound OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 description 1
- DXRFZHILMCWCNG-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-2-amine Chemical compound C1=CC=NC2=NC(N(C)C)=CC=C21 DXRFZHILMCWCNG-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000006459 hydrosilylation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical group C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000002444 silanisation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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Abstract
The present invention discloses a kind of chiral aza ring carbene precursor compound and its preparation method and application with benzimidazole skeleton, the present invention is reacted by five steps, it succinctly can effectively synthesize the novel chiral benzimidazole carbene precursor compound of series structure, and the oxygen-containing functional group containing lone pair electrons is introduced in chiral side chain substituent group, such ligand can be used as bidentate ligand to form complex compound with metal center, superior reactivity can be shown in metal catalysed reaction system, and is expected to obtain the catalysate of high enantiomter in asymmetric reaction.
Description
Technical field
The present invention relates to organic synthesis fields, and in particular to before a kind of chiral N-heterocyclic carbine with benzimidazole skeleton
Body compound and its preparation method and application.
Background technology
The research history of N-heterocyclic carbine (N-heterocyclic carbenes, NHCs) can trace back to 1962
Wanzlick is to its report for the first time, but until NHC monomers-imidazoles-of the isolated stabilization for the first time such as Arduengo in 1991
The research of 2- carbenes, NHCs ligands just attracts wide public concern.With Phosphine ligands comparatively, azepine carbenes have following spy
Point：1) π acceptances electron-donating and weaker stronger σ enable NHC to form more stable metal complex with transition metal
Object, and show better air and thermodynamic stability；It is 2) different from the space layout of Phosphine ligands " edge-to-face " institute,
The penta azacyclo carbenes mostly space structure with wedge hither plane, electrical factor and space layout can detach relatively
It is independent.Based on this, nitrogen heterocycle carbine ligand is played an increasingly important role in organic chemistry and Organometallic Chemistry field,
The catalytic performance of nitrogen heterocycle carbine ligand alreadys exceed traditional Phosphine ligands in many important reactions.
For now, the either monodentate or bidentate chirality NHC ligands that domestic and international seminar is developed, are tied substantially
Structure unit is based primarily upon the structures such as pentacyclic imidazoles or glyoxalidine, wherein the benzimidazole as one of representative skeleton
Carbenes research is less, is still in the starting stage.
The chemical displacement value of Cabbeen carbon is 231.47ppm in benzimidazole carbenes carbon spectrum, with unsaturated imidazole carbenes δ
(CNHC~210-220ppm) there were significant differences, closer to the chemical shift δ C of saturated imidazolinium quinoline Cabbeen carbonNHC~240ppm,
Speculate that this deshielding effect of carbene center may be attributed to the reduction of five-membered ring electron delocalization.In addition five yuan in such ligand
The geometric parameter of ring is also in the range of the value of saturated imidazolinium quinoline -2- carbenes, the C-C bond distance of C=C bond distance and saturated imidazolinium ring
It is close.
1999, Hahn et al. reported benzimidazole card for the first time on Chemistry-A European Journal
The synthesis of guest's ligand, and it is electrically inquired into structure feature, structure is as follows.
The research of chiral benzimidazole carbenes starts from 2001, and Diver seminars are first on Organic Letters
The secondary N atoms that report are linked with the benzimidazole carbene precursor salt of chiral side chain, but do not apply in asymmetric catalysis
Among, such chiral carbene precursor salt structure is as follows.
2003, the Jung seminars of University of Southern California were in Angewandte Chemie International
Report chiral tridentate benzimidazole Cabbeen palladium complex and its dimer that a kind of structure has much characteristic on Edition, and
Excellent enantioselectivity (ee is obtained in asymmetric oxidation Heck reactions>90%), structure is as follows.Subsequent Sakaguchi classes
The chiral ligand of same type is applied to the asymmetry of the ketone of the asymmetric hydrosilylation reaction of the ketone of iridium catalysis, ruthenium catalysis by topic group
Hydrogen transfer reaction, asymmetric conjugated reaction reaction of unsaturated ketenes of copper catalysis etc., achieve relatively good mapping selection
Property.
During 2003 to 2013, the Shi Min seminars of Chinese Academy of Sciences's Shanghai Institute of Organic Chemistry have axis by what they designed
Chiral benzimidazole carbenes are applied to transition metal-catalyzed a variety of asymmetric reactions, include the asymmetric hydrogen of rhodium catalysis
Silanization reaction, palladium chtalyst unsaturated ketenes asymmetric conjugated reaction reaction, palladium chtalyst imines asymmetric addition it is anti-
It answers, the reactions such as the asymmetric oxidation Kinetic Resolution of the alcohol of palladium chtalyst, achieves preferable enantioselectivity.The knot of such ligand
Structure is as follows.
Recently, the design of this seminar has synthesized serial new chiral benzimidazole carbene precursor salt, and in the virtue of rhodium catalysis
Medium enantioselectivity on the upper side is obtained in the not addition reaction of fragrant aldehyde, the chiral diaryl that structure series plays an important roll is secondary
Alcoholic compound.
The development course of benzimidazole carbenes is made a general survey of, which is still in the starting stage.Nevertheless, such skeleton
Carbenes partially catalyzed reaction in application shown certain advantage.Therefore, new chiral benzimidazole is developed
The synthetic method of carbenes and its metal complex is of great significance, and can not only enrich the culvert of carbene chemistry taxology itself
Justice, and can apply to asymmetric reaction and reduce the production cost of part chiral drug synthetic intermediate.
Invention content
The purpose of the present invention is by a succinct organic synthesis route, develop a kind of hand with benzimidazole skeleton
Property aza ring carbene precursor compound and its preparation method and application, to expand it in pharmaceutical intermediate synthetic reaction and organic
Application category in asymmetric catalysis synthesis.
A kind of chiral aza ring carbene precursor compound with benzimidazole skeleton, which is characterized in that the chirality azepine
Ring carbene precursor compound is：
Or its enantiomter
Wherein,
R1Selected from phenyl, benzyl, tertiary butyl, isopropyl, methyl, isobutyl group；
R2Selected from phenyl, 1- naphthalenes, 2- naphthalenes, benzyl, isopropyl, tertiary butyl and cyclohexyl；
R3Selected from hydrogen, 1- naphthoyls, 2- naphthoyls, 2,4,6- trimethylbenzoyls, to methoxybenzoyl base,
To tert-butyl-benzoyl；
R4Selected from chlorion, bromide ion, tetrafluoroborate ion, hexafluorophosphoricacid acid ions.
Preferably, the structure of the compound is selected from：
A kind of preparation method of chiral aza ring carbene precursor compound as described above, which is characterized in that this method packet
Include following steps：
(I) in aprotic solvent, chiral amino alcohol and tert-butyl chloro-silicane are in 4- as shown in general formula (I)
It is reacted under dimethylamino naphthyridine and triethylamine effect, then collection type (II) compound, reaction formula from reaction product
It is as follows：
(II) in aprotic solvent, will as shown in general formula (II) TBS protect amine alcohol compound and 1,2 dibromobenzenes,
It heats and is reacted under alkali and catalyst action, then collection type (III) compound from reaction product；
(III) in aprotic solvent, optical voidness 2- bromobenzenes aminated compounds and aromatic amine as shown in general formula (III)
Compound is heated under alkali and catalyst action and is reacted, then collection type (IV) compound from reaction product, and reaction is logical
Formula is as follows：
(IV) is dissolved in trimethyl orthoformate or orthoformic acid in aprotic solvent, by the chiral diamine as shown in general formula (IV)
Triethyl is reacted, then collection type (V-A) compound from reaction product under lewis acid effect；Reaction formula is such as
Under：
(V) reacts aza ring carbene precursor salt and acyl chlorides as shown in general formula (V-A) under alkaline condition, so
Collection type (V-B) compound, reaction formula are as follows from reaction product afterwards：
Preferably, the step (I) Chinese style (I) compound and the molar ratio of tert-butyl chloro-silicane are 1:1.1
Reaction temperature is 20~30 DEG C of room temperature, and the reaction time is 3~5 hours.
Preferably, the reaction temperature of the step (II) is 80~120 DEG C, and the reaction time is 5~12 hours, formula (II)
Compound, 1,2 dibromobenzenes, catalyst, alkali molar ratio be 1.2:1:0.1~0.01:1~2；The preferred tert-butyl alcohol of the alkali
Sodium, potassium tert-butoxide.
Preferably, the reaction temperature of the step (III) is 80~120 DEG C, and the reaction time is 12~16 hours, formula
(III) compound, aromatic amine compounds, catalyst, alkali molar ratio be 1:1.2:0.1~0.05:2~3；The alkali is excellent
Select sodium tert-butoxide, potassium tert-butoxide.
Preferably, the reaction temperature of the step (IV) is 80~120 DEG C, and the reaction time is 5~20 hours, formula (IV)
Compound, lewis acidic molar ratio are 1:1~10.
A kind of application of chiral aza ring carbene precursor compound as described above, which is characterized in that the compound is used as
The catalyst reacted as follows：
Wherein, Ar is respectively phenyl, substituted-phenyl, 1- naphthalenes or 2- naphthalenes；The reaction process of the reaction is as follows：In non-matter
In sub- solution, by palladium and the aza ring carbene precursor compound, 4- benzyl pyridines, the chemical combination as shown in general formula (VI)
Object reacts under alkali effect, then collection type (VII) compound from reaction product；Reaction temperature is 60-80 DEG C, the reaction time
For 12-18h, wherein 4- benzyl pyridines, (VI) compound, alkali, aza ring carbene precursor compound, the molar ratio of palladium is 1:
1.2:1:3:0.075:0.05。
Preferably, the aprotic solvent is benzene,toluene,xylene, tetrahydrofuran, glycol dimethyl ether and Isosorbide-5-Nitrae-two
Any one of six ring of oxygen, alkali used are sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol lithium, two (trimethyl silicon substrate) potassamides, two
Any one of (trimethyl silicon substrate) Sodamide, two (trimethyl silicon substrate) lithium amides.
A kind of application of chiral aza ring carbene precursor compound as described in claim 1, which is characterized in that the chemical combination
Object is used as the catalyst reacted as follows：
Wherein, Ar1And Ar2Respectively phenyl, substituted-phenyl, 1- naphthalenes, 2- naphthalenes etc.；The reaction process of the reaction is as follows：
In aprotic solvent, sequentially add such as general formula (VIII) compound represented, nickel metal and the aza ring carbene precursor
Object is closed, is eventually adding such as general formula (Ⅸ) compound represented, then collection type (Ⅹ) compound from reaction product.Reaction condition
For：24-50 DEG C of reaction temperature, reaction time 1-10h, wherein (VIII) compound, (Ⅸ), azepine carbene precursor compound, gold
The molar ratio for belonging to nickel is 1:1.2:0.05:0.05.
Beneficial effects of the present invention：
The present invention is reacted by five steps, succinctly can effectively synthesize the novel chiral benzimidazole carbene precursor of series structure
Compound, and the oxygen-containing functional group (hydroxyl obtains ester group) containing lone pair electrons is introduced in chiral side chain substituent group, such ligand can
To form complex compound as bidentate ligand and metal center, superior reaction can be shown in metal catalysed reaction system and is lived
Property, and be expected to obtain the catalysate of high enantiomter in asymmetric reaction.
Specific implementation mode
The present invention is described in detail below according to preferred embodiment, the objects and effects of the present invention will become more apparent, with
Under in conjunction with the embodiments, the present invention will be described in further detail.It should be appreciated that specific embodiment described herein is only used
To explain the present invention, it is not intended to limit the present invention.
The synthetic route of the chiral aza ring carbene precursor compound of the present invention is as follows：
(I) tert-butyl chloro-silicane, 4-dimethylaminopyridine；(II) 1,2- dibromobenzenes, BINAP, palladium metal, alkali
(sodium tert-butoxide, potassium tert-butoxide etc.)；(III) arylamine, BINAP, palladium metal, alkali (sodium tert-butoxide, potassium tert-butoxide etc.)；(IV) is former
Formic acid triethyl or trimethyl orthoformate, ammonium salt；(v) triethylamine, acyl chlorides.
The representative synthetic method (logical method 1) of compound ii：
4mmol chemical compounds Is (1eq), 8mmol triethylamines (2eq) are dissolved in dry methylene chloride (40mL), are stirred at room temperature
After five minutes, 4.4mmol tert-butyl chloro-silicanes (1.1eq) are added, continue stirring after five minutes, 4mmol 4- diformazans are added
Aminopyridine (1eq), after being stirred 3 hours at 20 DEG C, by reaction solution evaporated under reduced pressure, mixture column chromatography for separation (CH2Cl2:CH3OH
=80:1~50:1) product II is obtained.
The representative synthetic method (logical method 2) of compound III：
By 0.02mmol tris(dibenzylideneacetone) dipalladiums (1.0%eq), 0.04mmol (±) -2,2'- it is double-(diphenyl phosphine
Base) -1,1'- dinaphthalenes (2.0%eq) and 2.6mmol sodium tert-butoxides (1.3eq) three mixing, be added again steam toluene (15 mL), stir
It mixes down and sequentially adds 2mmol 1,2- dibromobenzenes (1eq) and 2.4mmol compound iis (1.2eq) stir 12 hours at 95 DEG C, instead
After answering, reaction solution is filtered, evaporated under reduced pressure, mixture column chromatography for separation (petroleum ether：Ethyl acetate=100:1) it is produced
Object III.
The representative synthetic method (logical method 3) of compounds Ⅳ：
By 0.15mmol palladiums (10%eq), 0.15mmol (±) -2,2'- it is double-(diphenyl phosphine) -1,1'- dinaphthalenes
(10% eq) is dissolved in and steams toluene (10mL) again, and 60 DEG C are stirred 10 minutes, and reaction solution is cooled to room temperature, and sequentially adds 1.5mmol
It is small to stir 12 at 80 DEG C for compound (III) (1eq), 1.8mmol arylamines (1.2eq) and 3.75mmol sodium tert-butoxides (2.5eq)
When, after reaction, reaction solution is filtered, evaporated under reduced pressure, mixture column chromatography for separation (petroleum ether：Ethyl acetate=50:1~
30:1) product IV is obtained.
The representative synthetic method (logical method 4) of compound V：
1mmol compounds Ⅳs (1eq) are dissolved in triethyl orthoformate (39mL), 8mmol concentrated hydrochloric acids are slowly added dropwise under stirring
(8eq) after being stirred at room temperature 30 minutes, 20 hours, after reaction, reaction solution evaporated under reduced pressure, by mixture column are stirred at 100 DEG C
Chromatography (CH2Cl2:CH3OH=50:1~30:1) product V is obtained.
Embodiment 1
The preparation and representation of compound ii -1：
Chemical compounds I -1 (521 μ L, 4mmol), triethylamine (1112 μ L, 8mmol) are dissolved in dry methylene chloride (40 mL)
In, it is stirred at room temperature after five minutes, tert-butyl chloro-silicane (663mg, 4.4mmol) is added, after continuing stirring 5 minutes, add
Enter 4-dimethylaminopyridine (489 μ L, 4mmol), reacts at room temperature 3 hours.Reaction solution evaporated under reduced pressure, by mixture column chromatography for separation
(CH2Cl2:CH3OH=80:1~50:1) II -1 656mg of yellow oil, yield 71%, are obtained.1H NMR(500MHz,
CDCl3)δ:3.76 (dd, J=9.8,3.2Hz, 1H), 3.40-3.31 (m, 1H), 2.57 (dd, J=8.8,3.2Hz, 1H),
0.91 (d, J=3.0Hz, 18H), 0.07 (s, 6H).
Embodiment 2
The preparation and representation of compound ii -2：
Preparation condition is the same as embodiment 1, yellow oil, yield 85%；1HNMR(500MHz,CDCl3)δ:7.38(dd,
J=8.3,1.3Hz, 2H), 7.36-7.32 (m, 2H), 7.29-7.24 (m, 1H), 4.08 (dd, J=8.4,3.9Hz, 1H),
3.73 (dd, J=9.8,4.0Hz, 1H), 3.53 (dd, J=9.8,8.4Hz, 1H), 0.94-0.86 (m, 9H), 0.03 (t, J=
2.2Hz,6H)。
Embodiment 3
The preparation and representation of compound ii -3：
Preparation condition is the same as embodiment 1, yellow oil, yield 88%；1HNMR(500MHz,CDCl3)δ:7.33–
7.28 (m, 2H), 7.25-7.19 (m, 3H), 3.59 (dd, J=9.7,4.4Hz, 1H), 3.45 (dd, J=9.7,6.5Hz,
1H), 3.10 (m, 1H), 2.80 (dd, J=13.4,5.3Hz, 1H), 2.52 (dd, J=13.4,8.4Hz, 1H), 0.94-0.91
(m,9H),0.09–0.05(m,6H)。
Embodiment 4
The preparation and representation of compound ii -4：
Preparation condition is the same as embodiment 1, yellow oil, yield 74%；1H NMR(500MHz,CDCl3)δ:3.64(dd,
J=9.8,4.0Hz, 1H), 3.43-3.35 (m, 1H), 2.57 (dd, J=10.9,6.9Hz, 1H), 1.61 (m, 1H), 0.93-
0.89(m,15H),0.06(s,6H)。
Embodiment 5
The preparation and representation of compound ii -5：
Preparation condition is the same as embodiment 1, yellow oil, yield 78%；1HNMR(500MHz,CDCl3)δ:3.66(dd,
J=9.8,3.7Hz, 1H), 3.42-3.35 (m, 1H), 2.70-2.63 (m, 1H), 1.57-1.49 (m, 1H), 1.43-1.36
(m,1H),1.18(m,1H),0.93–0.87(m,15H),0.06(s,6H)。
Embodiment 6
The preparation and representation of compound ii -6：
Preparation condition is the same as embodiment 1, yellow oil, yield 71%；1HNMR(500MHz,CDCl3)δ:3.51(dd,
J=9.7,4.2Hz, 1H), 3.27 (dd, J=9.7,7.5Hz, 1H), 2.97 (m, 1H), 1.01 (d, J=6.5Hz, 3H),
0.91-0.89 (s, 9H), 0.06 (d, J=2.8Hz, 6H).
Embodiment 7
The preparation and representation of compound III -1：
By tris(dibenzylideneacetone) dipalladium (18mg, 0.02mmol), 0.04mmol (±) -2,2'- it is double-(diphenyl phosphine
Base) -1,1'- dinaphthalenes (25mg, 0.04mmol) and sodium tert-butoxide (250mg, 2.6mmol) three be dissolved in toluene (15 mL), stir
It mixes down and sequentially adds 1,2- dibromobenzenes (241mg, 2mmol) and compound ii -1 (554mg, 2.4mmol), it is small that 12 are stirred at 95 DEG C
When, after reaction, reaction solution is filtered, evaporated under reduced pressure, mixture column chromatography for separation (petroleum ether：Ethyl acetate=100:1)
Obtain III -1463mg of colorless oil, yield 60%.1H NMR(500MHz,CDCl3)δ: 1H NMR(500MHz,CDCl3)
δ 7.42 (dd, J=7.9,1.5Hz, 1H), 7.16-7.09 (m, 1H), 6.72 (dd, J=8.3,0.9Hz, 1H), 6.51 (m,
1H), 4.72 (d, J=9.7Hz, 1H), 3.76 (m, 2H), 1.06 (s, 9H), 0.91-0.84 (m, 9H), 0.03-0.01 (m,
6H)。
Embodiment 8
The preparation and representation of compound III -2：
Preparation condition is the same as embodiment 7, colorless oil, yield 75%；1HNMR(500MHz,CDCl3)δ:7.43(dd,
J=7.9,1.5Hz, 1H), 7.35 (m, 4H), 7.28-7.25 (m, 1H), 6.99-6.93 (m, 1H), 6.52 (m, 1H), 6.33
(dd, J=8.2,1.4Hz, 1H), 4.42 (m, 1H), 3.95 (dd, J=10.1,4.2Hz, 1H), 3.72 (dd, J=10.2,
7.3Hz, 1H), 0.93-0.89 (m, 9H), 0.06 (d, J=2.9Hz, 3H), 0.01 (d, J=1.6Hz, 3H).
Embodiment 9
The preparation and representation of compound III -3：
Preparation condition is the same as embodiment 7, colorless oil, yield 77%；1HNMR(500MHz,CDCl3)δ:7.43(dd,
J=7.9,1.5Hz, 1H), 7.34-7.29 (m, 2H), 7.27-7.21 (m, 3H), 7.20-7.15 (m, 1H), 6.70 (dd, J=
8.2,1.3Hz, 1H), 6.57-6.53 (m, 1H), 4.78 (d, J=8.9Hz, 1H), 3.64-3.57 (m, 2H), 2.94 (d, J=
6.7Hz, 2H), 0.99-0.94 (m, 9H), 0.07 (t, J=2.5Hz, 6H).
Embodiment 10
The preparation and representation of compound III -4：
Preparation condition is the same as embodiment 7, colorless oil, yield 93%；1H NMR(500MHz,CDCl3)δ:7.40(m,
1H), 7.16-7.10 (m, 1H), 6.65 (dd, J=8.2,1.0Hz, 1H), 6.53-6.47 (m, 1H), 3.74 (dd, J=
10.1,3.7Hz, 1H), 3.63 (dd, J=10.1,5.0Hz, 1H), 3.25 (m, 1H), 2.06 (m, 1H), 1.01 (t, J=
7.0Hz, 6H), 0.91-0.89 (m, 9H), 0.03 (d, J=1.5Hz, 6H).
Embodiment 11
The preparation and representation of compound III -5：
Preparation condition is the same as embodiment 7, colorless oil, yield 80%；1HNMR(500MHz,CDCl3)δ:7.41(d, J
=7.8Hz, 1H), 7.13 (t, J=7.7Hz, 1H), 6.64 (d, J=8.2Hz, 1H), 6.51 (t, J=7.5Hz, 1H), 4.65
(d, J=8.9Hz, 1H), 3.71 (m, 2H), 3.32 (m, 1H), 1.84-1.75 (m, 1H), 1.67-1.58 (m, 1H), 0.96
(dd, J=15.5,7.3Hz, 6H), 0.90 (s, 9H), 0.03 (d, J=2.4Hz, 6H).
Embodiment 12
The preparation and representation of compound III -6：
Preparation condition is the same as embodiment 1, colorless oil, yield 88%；1HNMR(500MHz,CDCl3)δ:7.42(d, J
=7.9Hz, 1H), 7.16 (t, J=7.7Hz, 1H), 6.67 (d, J=8.2Hz, 1H), 6.54 (t, J=7.6Hz, 1H),
3.68-3.64 (m, 2H), 3.61 (s, 1H), 1.25 (d, J=6.3Hz, 3H), 0.92 (s, 9H), 0.07 (s, 6H).
Embodiment 13
The preparation and representation of compounds Ⅳ -1：
By palladium (34mg, 0.15mmol), 0.15mmol (±) -2,2'- it is double-(diphenyl phosphine) -1,1'- dinaphthalenes
(93mg, 0.15mmol) is dissolved in be steamed in toluene (10mL) again, and 60 DEG C are stirred 10 minutes, and reaction solution is cooled to room temperature, and is sequentially added
Compound III -1 (579mg, 1.5mmol), 2- naphthylamines (258mg, 1.8mmol) and sodium tert-butoxide (360mg, 3.75 mmol),
80 DEG C are stirred 12 hours, after reaction, reaction solution are filtered, evaporated under reduced pressure, mixture column chromatography for separation (petroleum ether：Acetic acid
Ethyl ester=50:1~30:1) IV -1 612mg of yellow jelly, yield 91% are obtained.1H NMR(500 MHz,CDCl3)δ:
7.73-7.66 (m, 2H), 7.56 (d, J=8.3Hz, 1H), 7.35 (t, J=7.1 Hz, 1H), 7.24 (t, J=7.1Hz, 1H),
7.19-7.09 (m, 2H), 7.04 (dd, J=8.7,2.1 Hz, 1H), 6.92 (s, 1H), 6.83 (d, J=8.1Hz, 1H), 6.67
(s,1H),3.68(m,2H),3.18 (s,1H),0.92(s,9H),0.80(s,9H),0.02–0.10(m,6H)。
Embodiment 14
The preparation and representation of compounds Ⅳ -2：
Preparation condition is the same as embodiment 13, white solid, yield 99%；1H NMR(500MHz,CDCl3)δ:7.73(dd,
J=8.2,5.2Hz, 2H), 7.61 (d, J=8.2Hz, 1H), 7.42-7.36 (m, 3H), 7.32 (t, J=7.4Hz, 2H),
7.29-7.23 (m, 1H), 7.19 (d, J=7.3Hz, 1H), 7.11 (dd, J=8.7,2.0Hz, 1H), 6.96 (dd, J=
16.4,8.2Hz, 2H), 6.72 (t, J=7.4Hz, 1H), 6.52 (d, J=7.3Hz, 1H), 4.45-4.39 (m, 1H), 3.85
(dd, J=10.1,4.1Hz, 1H), 3.63 (s, 1H), 0.72-0.68 (m, 9H), 0.02-0.01 (m, 3H), 0.13 (s, 3H).
Embodiment 15
The preparation and representation of compounds Ⅳ -3：
Preparation condition is the same as embodiment 13, yellow jelly, yield 97%；1H NMR(500MHz,CDCl3)δ:7.70
(dd, J=14.4,8.4Hz, 2H), 7.55 (d, J=8.2Hz, 1H), 7.36 (t, J=7.1Hz, 1H), 7.26-7.13 (m,
8H), 6.99 (dd, J=8.7,1.8Hz, 1H), 6.86 (d, J=6.8Hz, 2H), 6.74 (t, J=7.1Hz, 1H), 3.59
(dd, J=9.9,3.1Hz, 1H), 3.50 (dd, J=9.9,4.8Hz, 1H), 2.93-2.81 (m, 2H), 0.80 (s, 9H) ,-
0.07 (d, J=27.5Hz, 6H).
Embodiment 16
The preparation and representation of compounds Ⅳ -4：
Preparation condition is the same as embodiment 13, yellow jelly, yield 87%；1H NMR(500MHz,CDCl3)δ:7.70(t,
J=9.3Hz, 2H), 7.56 (d, J=8.3Hz, 1H), 7.35 (t, J=7.5Hz, 1H), 7.24 (t, J=7.4Hz, 1H),
7.19-7.11 (m, 2H), 7.04 (d, J=8.8Hz, 1H), 6.91 (s, 1H), 6.79 (d, J=7.9Hz, 1H), 6.68 (t, J
=7.3Hz, 1H), 3.68 (dd, J=10.0,3.6Hz, 1H), 3.55 (dd, J=10.0,5.3Hz, 1H), 3.27 (d, J=
4.2Hz, 1H), 1.99 (dd, J=13.2,6.5 Hz, 1H), 0.92 (d, J=6.7Hz, 3H), 0.87 (d, J=6.7Hz, 3H),
0.80(s,9H),0.03 (s,3H),0.08(s,3H)。
Embodiment 17
The preparation and representation of compounds Ⅳ -5：
Preparation condition is the same as embodiment 13, green glue object, yield 98%；1H NMR(500MHz,CDCl3)δ:7.70(t,
J=8.5Hz, 2H), 7.57 (d, J=8.1Hz, 1H), 7.36 (t, J=7.4Hz, 1H), 7.28-7.23 (m, 3H), 7.07 (d,
J=16.2Hz, 2H), 6.99 (s, 1H), 6.83 (s, 1H), 3.69 (d, J=42.2 Hz, 2H), 1.49 (dd, J=60.0,
34.7Hz, 4H), 0.96-0.84 (m, 6H), 0.81 (s, 9H), 0.05 (dd, J=22.0,10.0Hz, 6H).
Embodiment 18
The preparation and representation of compounds Ⅳ -6：
Preparation condition is the same as embodiment 13, yellow jelly, yield 96%；1H NMR(500MHz,CDCl3)δ:7.70(t,
J=8.8Hz, 2H), 7.56 (d, J=8.2Hz, 1H), 7.36 (t, J=7.5Hz, 1H), 7.24 (t, J=7.4Hz, 1H),
7.20 (d, J=7.6Hz, 1H), 7.14 (t, J=7.6Hz, 1H), 7.05 (d, J=8.6Hz, 1H), 6.92 (s, 1H), 6.83
(d, J=8.0Hz, 1H), 6.74 (t, J=7.4Hz, 1H), 3.67-3.58 (m, 2H), 3.58-3.51 (m, 1H), 1.19 (d, J
=5.9Hz, 3H), 0.79 (s, 9H), 0.05 (d, J=14.7Hz, 6H).
Embodiment 19
The preparation and representation of compound V -1：
Compounds Ⅳ -1 (448mg, 1mmol) is dissolved in triethyl orthoformate (39mL), concentrated hydrochloric acid is slowly added dropwise under stirring
(662 μ L, 8mmol after being stirred at room temperature 30 minutes, stir 20 hours at 100 DEG C, after reaction, by reaction solution evaporated under reduced pressure,
Mixture column chromatography for separation (CH2Cl2:CH3OH=50:1~30:1) V -1315mg of white solid, yield 83% are obtained.1H
NMR(500MHz,DMSO)δ:10.52 (s, 1H), 8.57 (s, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.32 (d, J=
8.8Hz, 1H), 8.19-8.13 (m, 2H), 8.02 (dd, J=8.7,1.9 Hz, 1H), 7.95 (d, J=8.2Hz, 1H), 7.81-
7.76 (m, 1H), 7.76-7.71 (m, 3H), 5.38 (t, J=5.6Hz, 1H), 4.32-4.19 (m, 1H), 4.09 (m, 1H),
1.07(s,9H)；13C NMR(125 MHz,DMSO)δ142.21,134.31,133.61,133.17,131.28,131.11,
130.57,128.88,128.52, 128.45,128.20,127.91,127.52,125.32,123.46,115.24,
114.07,70.07,59.51,55.38, 35.04,27.12。
Embodiment 20
The preparation and representation of compound V -2：
Preparation condition is the same as embodiment 19, white gum object, yield 93%；1H NMR(500MHz,DMSO)δ:10.69
(s, 1H), 8.59 (d, J=2.0Hz, 1H), 8.33 (d, J=8.9Hz, 1H), 8.20-8.12 (m, 2H), 8.09-8.02 (m,
2H),8.00–7.94(m,1H),7.77–7.70(m,4H),7.69–7.65(m,2H), 7.48–7.37(m,3H),6.32–
6.22(m,1H),4.57(m,1H),4.24–4.17(m,1H)；13C NMR(125MHz,DMSO)δ142.43,137.87,
135.51,133.63,133.20,131.89,131.83, 131.10,130.71,129.43,128.91,128.52,
128.23,128.16,128.09,127.67,125.82, 125.15,123.24,120.83,114.86,114.44,
112.51,64.60,62.47,25.94。
Embodiment 21
The preparation and representation of compound V -3：
Preparation condition is the same as embodiment 19, white gum object, yield 93%；1H NMR(500MHz,DMSO)δ:10.63
(s, 1H), 8.48 (d, J=2.0Hz, 1H), 8.32 (d, J=8.8Hz, 1H), 8.22 (d, J=7.8Hz, 1H), 8.20-8.13
(m, 2H), 7.96-7.87 (m, 2H), 7.76-7.65 (m, 4H), 7.36 (d, J=7.3Hz, 2H), 7.26 (t, J=7.6Hz,
2H), 7.17 (t, J=7.3Hz, 1H), 5.62 (t, J=6.2Hz, 1H), 4.03-3.86 (m, 2H), 3.48 (m, 2H)；13C
NMR(125MHz,DMSO)δ142.48, 137.15,133.56,133.20,132.30,131.29,131.04,130.84,
129.57,129.01,128.91, 128.52,128.47,128.25,127.91,127.40,127.33,124.85,
123.04,114.81,114.00, 79.77,62.58,61.92,36.09。
Embodiment 22
The preparation and representation of compound V -4：
Preparation condition is the same as embodiment 19, white gum object, yield 85%；1H NMR(500MHz,DMSO)δ:10.47
(s, 1H), 8.55 (s, 1H), 8.33 (d, J=8.7Hz, 2H), 8.16 (d, J=2.7Hz, 2H), 7.99 (dd, J=17.2,
8.4Hz, 2H), 7.77 (m, 4H), 5.46 (t, J=5.8Hz, 1H), 4.82 (d, J=7.0 Hz, 1H), 4.09 (m, 1H), 3.91
(dd, J=7.6,4.9Hz, 1H), 1.15 (d, J=6.5Hz, 3H), 0.88 (t, J=7.8Hz, 3H)；13C NMR(125MHz,
DMSO)δ142.31,133.58,133.20,132.81, 131.62,131.16,130.66,128.87,128.51,128.42,
128.20,127.97,127.49,125.12, 123.29,114.94,114.20,67.49,60.66,29.40,19.77,
19.74。
Embodiment 23
The preparation and representation of compound V -5：
Preparation condition is the same as embodiment 19, white gum object, yield 87%；1H NMR(500MHz,DMSO)δ:10.44
(s, 1H), 8.52 (s, 1H), 8.32 (dd, J=8.4,3.9Hz, 2H), 8.18-8.12 (m, 2H), 8.01-7.95 (m, 2H),
7.82-7.70 (m, 4H), 5.40 (t, J=5.9Hz, 1H), 4.86 (dd, J=11.4,4.8Hz, 1H), 4.08 (m, 1H),
3.89 (m, 1H), 2.40-2.31 (m, 1H), 1.39-1.29 (m, 1H), 1.11 (d, J=6.7Hz, 3H), 0.83 (t, J=
7.3Hz,3H)；13C NMR(125MHz,DMSO)δ 142.34,133.58,133.19,132.70,131.65,131.16,
130.65,128.88,128.51,128.42, 128.20,127.98,127.54,125.10,123.30,114.85,
114.25,65.86,60.56,35.06,25.35, 15.62,10.97。
Embodiment 24
The preparation and representation of compound V -6：
Preparation condition is the same as embodiment 19, white gum object, yield 82%；1H NMR(500MHz,DMSO)δ:10.42
(s, 1H), 8.50 (d, J=2.0Hz, 1H), 8.30 (dd, J=14.9,8.5Hz, 2H), 8.18-8.12 (m, 2H), 7.99-
7.92 (m, 2H), 7.80-7.70 (m, 4H), 5.47 (t, J=6.2Hz, 1H), 3.87 (t, J=5.6Hz, 2H), 1.71 (d, J
=6.9Hz, 3H)；13C NMR(125MHz,DMSO)δ142.29, 133.56,133.21,132.03,131.77,131.20,
130.72,128.87,128.51,128.42,128.21, 127.86,127.28,124.97,123.17,115.03,
114.05,63.73,57.25,16.44。
Embodiment 25
The embodiment is the Catalysis experiments of aza ring carbene precursor V -1~V -6, wherein V -1~V -6 structural formula
As follows, catalytic effect is as shown in table 1.
The preparation and representation of compound A-2：
Under the conditions of nitrogen protection, 0.015mmol aza ring carbene precursors are dissolved in 2mL dry toluenes, are added
After stirring 15 minutes, 0.6mmol bis- (trimethyl silicon substrate) Sodamide is added in 0.01mmol palladiums, and stirring after twenty minutes, will
0.4mmol compounds A-1,0.2mmol4- tertiary butyl bromobenzene is added in reaction solution, and 60 DEG C are reacted 12 hours.After the completion of reaction,
5 extractions of dripping are added to go out reaction, takes a suction funnel to be encased inside diatomite, filters, three times with ethyl acetate elution, merging organic phase
Solvent, column chromatography for separation (petroleum ether are removed in decompression rotation afterwards:Ethyl acetate=3:1) product A-2, yield are obtained：95%；1H NMR
(500 MHz,CDCl3):δ 8.50 (d, J=6.0Hz, 2H), 7.34-7.21 (m, 5H), 7.10 (d, J=7.5Hz, 2H),
7.07–6.98(m,4H),5.46(s,1H),1.30(s,9H)ppm；13C NMR(125MHz,CDCl3):δ 153.2,150.0,
149.9,142.6,139.1,129.5,129.1,128.7,127.0,125.7,124.8,56.0, 34.6,31.5。
The catalysis yield of 1 aza ring carbene precursor V -1~V -6 of table
It will appreciated by the skilled person that the foregoing is merely the preferred embodiment of invention, it is not used to limit
System invention, although invention is described in detail with reference to previous examples, for those skilled in the art, still
It can modify to the technical solution of aforementioned each case history or equivalent replacement of some of the technical features.It is all
Within the spirit and principle of invention, modification, equivalent replacement for being made etc. should be included within the protection domain of invention.
Claims (10)
1. a kind of chiral aza ring carbene precursor compound with benzimidazole skeleton, which is characterized in that the chirality azacyclo-
Carbene precursor compound is：
Or its enantiomter：
Wherein,
R1Selected from phenyl, benzyl, tertiary butyl, isopropyl, methyl, isobutyl group.
R2Selected from phenyl, 1- naphthalenes, 2- naphthalenes, benzyl, isopropyl, tertiary butyl and cyclohexyl.
R3Selected from hydrogen, 1- naphthoyls, 2- naphthoyls, 2,4,6- trimethylbenzoyls, to methoxybenzoyl base, to uncle
Butylbenzoyl.
R4Selected from chlorion, bromide ion, tetrafluoroborate ion, hexafluorophosphoricacid acid ions.
2. the chiral aza ring carbene precursor compound according to claim 1 with benzimidazole skeleton, feature exist
In the structure of the compound is selected from：
3. a kind of preparation method of chiral aza ring carbene precursor compound as described in claim 1, which is characterized in that the party
Method includes the following steps：
(I) in aprotic solvent, chiral amino alcohol and tert-butyl chloro-silicane are in 4- diformazan ammonia as shown in general formula (I)
It is reacted under yl pyridines and triethylamine effect, then collection type (II) compound, reaction formula are as follows from reaction product：
(II) in aprotic solvent, the TBS as shown in general formula (II) protects amine alcohol compound and 1,2 dibromobenzenes, in alkali
It is reacted with heating under catalyst action, then collection type (III) compound from reaction product；
(III) in aprotic solvent, optical voidness 2- bromobenzenes aminated compounds and aromatic amine chemical combination as shown in general formula (III)
Object is heated under alkali and catalyst action and is reacted, then collection type (IV) compound from reaction product, and reaction formula is such as
Under：
(IV) is dissolved in trimethyl orthoformate or primitive nail triethylenetetraminehexaacetic acid in aprotic solvent, by the chiral diamine as shown in general formula (IV)
Ester is reacted, then collection type (V-A) compound from reaction product under lewis acid effect；Reaction formula is as follows：
(V) reacts aza ring carbene precursor salt and acyl chlorides as shown in general formula (V-A) under alkaline condition, then from
Collection type (V-B) compound, reaction formula are as follows in reaction product：
4. preparation method according to claim 3, which is characterized in that step (I) Chinese style (I) compound and tertiary fourth
The molar ratio of base dimethylchlorosilane is 1:1.1, reaction temperature is 20~30 DEG C of room temperature, and the reaction time is 3~5 hours.
5. preparation method according to claim 4, which is characterized in that the reaction temperature of the step (II) be 80~
120 DEG C, the reaction time be 5~12 hours, formula (II) compound, 1,2 dibromobenzenes, catalyst, alkali molar ratio be 1.2:1:0.1
~0.01:1~2；The preferred sodium tert-butoxide of the alkali, potassium tert-butoxide.
6. preparation method according to claim 5, which is characterized in that the reaction temperature of the step (III) be 80~
120 DEG C, the reaction time be 12~16 hours, formula (III) compound, aromatic amine compounds, catalyst, alkali molar ratio be 1:
1.2:0.1~0.05:2~3；The preferred sodium tert-butoxide of the alkali, potassium tert-butoxide.
7. preparation method according to claim 6, which is characterized in that the reaction temperature of the step (IV) be 80~
120 DEG C, the reaction time is 5~20 hours, and formula (IV) compound, lewis acidic molar ratio are 1:1~10.
8. a kind of application of chiral aza ring carbene precursor compound as described in claim 1, which is characterized in that the compound
As the catalyst reacted as follows：
Wherein, Ar is respectively phenyl, substituted-phenyl, 1- naphthalenes or 2- naphthalenes；The reaction process of the reaction is as follows：Non-proton molten
In liquid, palladium and the aza ring carbene precursor compound, 4- benzyl pyridines, such as general formula (VI) compound represented are existed
Alkali effect is lower to react, then collection type (VII) compound from reaction product；Reaction temperature is 60-80 DEG C, reaction time 12-
18h, wherein 4- benzyl pyridines, (VI) compound, alkali, aza ring carbene precursor compound, the molar ratio of palladium are 1:1.2:
1:3:0.075:0.05。
9. the application of chirality aza ring carbene precursor compound as claimed in claim 8, which is characterized in that described is non-proton
Solvent is any one of benzene,toluene,xylene, tetrahydrofuran, glycol dimethyl ether and Isosorbide-5-Nitrae-dioxane, and alkali used is
Sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol lithium, two (trimethyl silicon substrate) potassamides, two (trimethyl silicon substrate) Sodamides, two (front threes
Any one of base silicon substrate) lithium amide.
10. a kind of application of chiral aza ring carbene precursor compound as described in claim 1, which is characterized in that the chemical combination
Object is used as the catalyst reacted as follows：
Wherein, Ar1And Ar2Respectively phenyl, substituted-phenyl, 1- naphthalenes, 2- naphthalenes etc.；The reaction process of the reaction is as follows：Non-
In proton solution, sequentially add such as general formula (VIII) compound represented, nickel metal and the aza ring carbene precursor compound,
It is eventually adding such as general formula (Ⅸ) compound represented, then collection type (Ⅹ) compound from reaction product.Reaction condition is：Instead
Answer 24-50 DEG C of temperature, reaction time 1-10h, wherein (VIII) compound, (Ⅸ), azepine carbene precursor compound, metallic nickel
Molar ratio is 1:1.2:0.05:0.05.
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