CN113302172B - 手性四芳基甲烷的对映选择性制备方法 - Google Patents
手性四芳基甲烷的对映选择性制备方法 Download PDFInfo
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- CN113302172B CN113302172B CN202080008861.8A CN202080008861A CN113302172B CN 113302172 B CN113302172 B CN 113302172B CN 202080008861 A CN202080008861 A CN 202080008861A CN 113302172 B CN113302172 B CN 113302172B
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- heterocycloalkyl
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- 238000000034 method Methods 0.000 claims abstract description 131
- 125000003118 aryl group Chemical group 0.000 claims description 139
- 125000001072 heteroaryl group Chemical group 0.000 claims description 134
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 91
- 125000000217 alkyl group Chemical group 0.000 claims description 88
- -1 9-phenanthryl Chemical group 0.000 claims description 85
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 65
- 125000001188 haloalkyl group Chemical group 0.000 claims description 63
- 229910052739 hydrogen Inorganic materials 0.000 claims description 53
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 53
- 239000001257 hydrogen Substances 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 50
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- 239000000203 mixture Substances 0.000 claims description 37
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- 239000007848 Bronsted acid Substances 0.000 claims description 34
- 125000003342 alkenyl group Chemical group 0.000 claims description 26
- 239000012038 nucleophile Substances 0.000 claims description 25
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 24
- 238000007345 electrophilic aromatic substitution reaction Methods 0.000 claims description 21
- 125000000304 alkynyl group Chemical group 0.000 claims description 20
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 19
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- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
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- 125000004429 atom Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 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 3
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
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- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 5
- 238000006362 organocatalysis Methods 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 213
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- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 43
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- 238000012216 screening Methods 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- TVCXVUHHCUYLGX-UHFFFAOYSA-N 2-Methylpyrrole Chemical compound CC1=CC=CN1 TVCXVUHHCUYLGX-UHFFFAOYSA-N 0.000 description 11
- ANUAVZDARZVWGB-UHFFFAOYSA-N 4-[hydroxy-(2-methoxyphenyl)-phenylmethyl]phenol Chemical compound OC(C1=CC=C(C=C1)O)(C1=CC=CC=C1)C1=C(C=CC=C1)OC ANUAVZDARZVWGB-UHFFFAOYSA-N 0.000 description 11
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- DYMRYCZRMAHYKE-UHFFFAOYSA-N n-diazonitramide Chemical compound [O-][N+](=O)N=[N+]=[N-] DYMRYCZRMAHYKE-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- YTCFBKIARZGTST-UHFFFAOYSA-N (2-methoxyphenyl)-phenyl-(3-phenyl-1H-indol-2-yl)methanol Chemical compound COC1=C(C=CC=C1)C(O)(C=1NC2=CC=CC=C2C=1C1=CC=CC=C1)C1=CC=CC=C1 YTCFBKIARZGTST-UHFFFAOYSA-N 0.000 description 8
- 125000005605 benzo group Chemical group 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
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- 229910002027 silica gel Inorganic materials 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 125000001041 indolyl group Chemical group 0.000 description 6
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- 125000003636 chemical group Chemical group 0.000 description 5
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- 150000003509 tertiary alcohols Chemical class 0.000 description 5
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 4
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 4
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- 150000001299 aldehydes Chemical group 0.000 description 3
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- 238000010521 absorption reaction Methods 0.000 description 1
- PHENPABYBHPABM-UHFFFAOYSA-N acetic acid;octane Chemical compound CC(O)=O.CCCCCCCC PHENPABYBHPABM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- XWHTVJSRZQUVOT-UHFFFAOYSA-N aminosulfanyl-N-nitroiminophosphonamidic acid Chemical group NSP(=O)(N=N[N+](=O)[O-])O XWHTVJSRZQUVOT-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- HFACYLZERDEVSX-UHFFFAOYSA-N benzidine Chemical class C1=CC(N)=CC=C1C1=CC=C(N)C=C1 HFACYLZERDEVSX-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 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 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- XNMQEEKYCVKGBD-UHFFFAOYSA-N dimethylacetylene Natural products CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 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 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004780 naphthols Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000005693 optoelectronics Effects 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000001394 phosphorus-31 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000007398 protein translocation Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003233 pyrroles Chemical class 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
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 150000005082 selenophenes Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- RBRCCWBAMGPRSN-UHFFFAOYSA-N thieno[2,3-d][1,3]thiazole Chemical compound S1C=NC2=C1C=CS2 RBRCCWBAMGPRSN-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- UMHFSEWKWORSLP-UHFFFAOYSA-N thiophene 1,1-dioxide Chemical compound O=S1(=O)C=CC=C1 UMHFSEWKWORSLP-UHFFFAOYSA-N 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D207/30—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
- C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- 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
- B01J31/0255—Phosphorus containing compounds
- B01J31/0257—Phosphorus acids or phosphorus acid esters
- B01J31/0258—Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
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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
- C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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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
- C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
本文提供了用于制备手性四芳基甲烷的对映选择性有机催化方法。
Description
相关申请的交叉引用
本申请要求2019年1月29日提交的美国临时申请第62/918,404号的优先权,出于所有目的,该申请的内容特此通过引用整体并入。
技术领域
本公开总体上涉及有机合成领域。更具体地,本公开涉及用于手性四芳基甲烷的对映选择性制备方法。
背景
四芳基甲烷由于其应用而在有机材料、药物、生命科学和超分子化学领域中引起了越来越多的关注,所述应用包括光电器件、功能材料框架、药物递送、制药和蛋白质移位检测。
目前,没有用于手性四芳基甲烷的催化不对称构建的直接方法。常规方法需要将手性四芳基甲烷制备为外消旋混合物并分离对映异构体,这导致不期望的对映异构体的损失和纯化步骤。四芳基甲烷的催化对映选择性制备在合成有机化学中仍然是非常理想但未能实现的目标。因此,需要克服上述挑战的合成手性四芳基甲烷的对映选择性催化方法。
总述
本文提供了一种利用有机催化对映选择性亲电芳香取代反应,以高收率和对映体过量(ee)制备结构多样的四芳基甲烷的方法。
在第一方面,本文提供了用于制备具有式I结构的四芳基甲烷的对映选择性方法:
其中Ar1、Ar2、Ar3、Ar4各自独立地为芳基或杂芳基;
该方法包括:
在手性布朗斯特酸的存在下,在促进亲电芳香取代反应的条件下,使式II的化合物:
与杂芳族亲核试剂接触,从而形成式I的化合物,其中式I的化合物是手性的。在第一实施方案中,本文提供了第一方面的方法,其中所述四芳基甲烷具有式Ia:
其中,
m和n各自独立地选自1、2、3或4;
Ar1是芳基和杂芳基;
Ar2是杂芳基;
R1和R2各自独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,氰化物,硝基,叠氮化物,-OR3,-OSi(R3)3,-O(C=O)R3,-(C=O)OR3,-O(C=O)OR3,-(C=O)R3,-N(R4)2,-N(R4)(C=O)R3,-(C=O)N(R4)2,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-(S=O)R3,-SO2R3,-SO2N(R4)2,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)3和-(P=O)(OR3)3组成的组;或两个R1与它们所连接的碳一起形成5-6元环烷基,杂环烷基,芳基或杂芳基;或两个R2与它们所连接的碳一起形成5-6元环烷基,杂环烷基,芳基或杂芳基;
R3选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基和杂芳基组成的组;并且
对于每个实例,R4独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基和杂芳基组成的组;或两个R4与它们所连接的氮一起形成3-6元杂环烷基;或一个R3和一个R4与它们所连接的原子一起形成4-6元杂环烷基;并且所述方法包括:
在手性布朗斯特酸的存在下,在促进亲电芳族取代反应的条件下,使式IIa的化合物:
与杂芳族亲核试剂接触,从而形成式Ia的化合物。在第二实施方案中,本文提供了的第一方面的方法,其中所述手性布朗斯特酸是手性磷酸。
在第三实施方案中,本文提供了第一方面的第二实施方案的方法,其中所述手性磷酸由式IIIa、式IIIb、式IIIc或式IIId表示:
其中Q是O、S或NSO2R16;
Z是O、S或Se;
R5和R5’各自独立地是氢,烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三芳基硅烷;
R6和R6’各自独立地是氢,烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三烷基硅烷;
R7和R7’各自独立地为烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三烷基硅烷;或R6'和R7'与它们所连接的碳一起形成5-6元环烷基或6元芳基,并且R6和R7与它们所相连的碳一起形成5-6元环烷基或6元芳基;
R14和R14′各自独立地是氢,烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三烷基硅烷;R15和R15’各自独立地是氢,烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三烷基硅烷;并且
R16是烷基或芳基。
在第四实施方案中,本文提供了第一方面的第三实施方案的方法,其中所述手性磷酸由式IIIe表示:
其中,R8为烷基、环烷基或芳基。
在第五实施方案中,本文提供了第一方面的第四实施方案的方法,其中R8是异丙基、环己基或苯基。
在第六实施方案中,本文提供了第一方面的第一实施方案的方法,其中式IIa的化合物由选自以下的结构表示:
其中,m是0、1、2或3;
p是0、1、2或3;
q是0、1或2;
A1选自由以下组成的组:
X是NR11、O、S或Se;
R1’选自由-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,
-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;或R1’和一个R1与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基;
每个R9独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,氰化物,硝基,叠氮化物,-OR3,-OSi(R3)3,-O(C=O)R3,-(C=O)OR3,-O(C=O)OR3,-(C=O)R3,-N(R4)2,-N(R4)(C=O)R3,-(C=O)N(R4)2,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-(S=O)R3,-SO2R3,-SO2N(R4)2,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)3和-(P=O)(OR3)3组成的组;
R9’选自由-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,
-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;或两个R9’与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基;并且
R10选自由烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3或-SeR3组成的组;并且R11是氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,-(C=O)OR3,-(C=O)R3,-(C=O)N(R4)2,-SO2R3或-SO2N(R4)2。
在第七实施方案中,本文提供了第一方面的第六实施方案的方法,其中Ar1选自由以下组成的组:
在第八实施方案中,本文提供了第一方面的第一实施方案的方法,其中所述杂芳族亲核试剂由式IV表示:
其中
t为0、1、2或3;
Y为NR13、O、S或Se;
每个R12独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,氰化物,硝基,叠氮化物,-OR3,-OSi(R3)3,-O(C=O)R3,-(C=O)OR3,-O(C=O)OR3,-(C=O)R3,-N(R4)2,-N(R4)(C=O)R3,-(C=O)N(R4)2,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-(S=O)R3,-SO2R3,-SO2N(R4)2,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)3,和-(P=O)(OR3)3组成的组;或两个R12与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基;并且
R13是氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,-(C=O)OR3,-(C=O)R3,-(C=O)N(R4)2,-SO2R3,或-SO2N(R4)2。
在第九实施方案中,本文提供了第一方面的第八实施方案的方法,其中Y为NR13;
每个R12独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,氰化物,硝基,叠氮化物,-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-SO2N(R4)2,-N(R4)SO2R3和-SeR3组成的组;或两个R12与它们所连接的碳一起形成6元环烷基或芳基;且
R13是氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基或杂芳基。
在第十实施方案中,本文提供了第一方面的第一实施方案的方法,其中式IIa的化合物由选自以下的结构表示:
其中
m为0、1、2或3;
p为0、1、2或3;
q为0、1或2;
Ar1选自由以下组成的组:
X为Se或NR11
R1’选自由-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,
-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;或R1’和一个R1与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基;
每个R9独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,氰化物,硝基,叠氮化物,-OR3,-OSi(R3)3,-O(C=O)R3,-(C=O)OR3,-O(C=O)OR3,-(C=O)R3,-N(R4)2,-N(R4)(C=O)R3,-(C=O)N(R4)2,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-(S=O)R3,-SO2R3,-SO2N(R4)2,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)和-(P=O)(OR3)3组成的组;
R9’选自由-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,
-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;或两个R9’与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基;
R10选自由烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基和卤化物组成的组;和
R11是氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基或杂芳基;且
所述杂芳族亲核试剂由式IV表示:
其中
t是0,、1、2或3;
Y是NR13;
每个R12独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,叠氮化物,-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;或两个R12与它们所连接的碳一起形成5-6元环烷基,杂环烷基,芳基或杂芳基;且
R13是氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基或杂芳基。
在第十一实施方案中,本文提供了第一方面的第十实施方案的方法,其中m是0或1;R1’是-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3或-O(C=O)N(R4)2;
Ar1选自:
其中
p是0或1;
q是0或1;
R9'选自-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,或-O(C=O)N(R4)2;
R10是芳基;并且所述杂芳族亲核试剂选自:
其中t为0或1;且
每个R12独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,叠氮化物,-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;或两个R12与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基。
在第十二实施方案中,本文提供了第一方面的第十一个实施方案的方法,其中手性布朗斯特酸由式IIIf或式IIIg表示:
其中R5和R5’中的每一个是烷基,芳基或三芳基硅烷。
在第十三实施方案中,本文提供了第一方面的第十二实施方案的方法,其中R5是2,4,6-(iPr)3C6H2-,2,4,6-Cy3C6H2-,1-萘基,9-蒽基,9-菲基,1-芘或2,6-iPr2-6-(9-蒽基)。
在第十四实施方案中,本文提供了第一方面的方法,其中在手性布朗斯特酸的存在下使式II的化合物与杂芳族亲核试剂接触的步骤发生在选自由氯苯,PhCF3,PhF,CCl4,CH2Cl2(DCM),CHCl3,PhMe和ClCH2CH2Cl(DCE)组成的组的溶剂中。
在第十五实施方案中,本文提供了第一方面的方法,其中相对于式II的化合物,手性布朗斯特酸以0.1%和25%之间的摩尔浓度存在。
在第十六实施方案中,本文提供了第一方面的方法,其中在手性布朗斯特酸的存在下使式II的化合物与杂芳族亲核试剂接触的步骤发生在-30℃和40℃之间的温度下。
在第十七实施方案中,本文提供了第一方面的方法,其中以40至99.9%的对映体过量(ee)制备具有式I的四芳基甲烷。
在第十八实施方案中,本文提供了第一方面的第九实施方案的方法,其中以80至97%的ee制备具有式I的四芳基甲烷。
在第十九实施方案中,本文提供了第一方面的方法,其中式II的化合物是外消旋混合物。
附图简要说明
当结合附图理解本公开的以下描述时,本公开的上述和其他目的和特征将变得明显,其中:
图1A描绘了根据本文所述方法的某些实施方案的示例性对映选择性亲电芳香取代反应。
图1B描绘了根据本文所述方法的某些实施方案的用作催化剂的示例性手性布朗斯特酸的化学结构。
图2描绘了在根据本文所述方法的某些实施方案的与4-(羟基(2-甲氧基苯基)(苯基)甲基)苯酚的模型亲电芳香取代反应中,筛选手性布朗斯特酸获得的实验结果。
图3描绘了在根据本文所述方法的某些实施方案的与4-(羟基(2-甲氧基苯基)(苯基)甲基)苯酚的模型亲电芳香取代反应中,筛选手性磷酸获得的实验结果。
图4描绘了在根据本文所述方法的某些实施方案的与4-(羟基(2-甲氧基苯基)(苯基)甲基)苯酚的模型亲电芳香取代反应中,筛选溶剂酸获得的实验结果。
图5描绘了在根据本文所述方法的某些实施方案的与4-(羟基(2-甲氧基苯基)(苯基)甲基)苯酚的模型亲电芳香取代反应中,筛选温度获得的实验结果。
图6描绘了在根据本文所述方法的某些实施方案的与4-(羟基(2-甲氧基苯基)(苯基)甲基)苯酚的模型亲电芳香取代反应中,筛选手性布朗斯特酸催化剂负载获得的实验结果。
图7描绘了在根据本文所述方法的某些实施方案的与(2-甲氧基苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇的模型亲电芳族取代反应中,筛选手性布朗斯特酸获得的实验结果。
图8描绘了在根据本文所述方法的某些实施方案的与(2-甲氧基苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇的模型亲电芳香取代反应中,筛选溶剂获得的实验结果。
图9描绘了在根据本文所述方法的某些实施方案的与(2-甲氧基苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇的模型亲电芳香取代反应中,筛选温度获得的实验结果。
图10描绘了在根据本文所述方法的某些实施方案的与(2-甲氧基苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇的模型亲电芳香取代反应中,筛选催化剂负载获得的实验结果。
图11描绘了在根据本文所述方法的某些实施方案的与(2-甲氧基苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇的模型亲电芳香取代反应中,筛选温度获得的实验结果。
图12描绘了在根据本文所述方法的某些实施方案的与杂芳族亲核试剂的亲电芳香取代反应中,筛选4-(羟基(Ar3)(Ar4)甲基)苯酚底物而获得的实验结果。
图13描绘了在根据本文所述方法的某些实施方案的与杂芳族亲核试剂的亲电芳族取代反应中,筛选(Ar3)(Ar4)(3-苯基-1H-吲哚-2-基)甲醇底物而获得的实验结果。
详细说明
定义
在整个申请中,其中组合物被描述为具有、包括或包含特定组分,或者其中方法被描述为具有、包括或包含特定过程步骤,可以预期的是,本教导的组合物也可以主要由所述组件组成或由所述组件组成,并且本教导的过程也可以主要由所述过程步骤组成或由所述过程步骤组成。
在本申请中,在要素或组件被表述为被包括在所列举的要素或组件的列表中和/或从列举的要素或组件的列表中选择的情况下,应当理解,该要素或组件可以是所列举的要素或组件中的任何一个,或要素或组件可以选自由两个或多个所列举的要素或组件组成的组。此外,应当理解,在不脱离本教导的精神和范围的情况下,本文所述的组合物、装置或方法的要素和/或特征可以以多种方式组合,无论本文是明确的还是隐含的。
除非另外特别说明,术语“包括(include)”,“包括(includes)”,“包括(including)”,“具有(have)”,“具有(has)”或“具有(having)”的使用通常应被理解为开放式和非限制性的。
除非另外特别说明,否则本文中的单数形式的使用包括复数形式(反之亦然)。另外,除非另外特别说明,否则在定量值之前使用术语“约”的情况下,本教导也包括特定的定量值本身。如本文所用,除非另外指出或推断,否则术语“约”是指与标称值相差±10%、±7%、±5%、±3%、±1%或±0%。
应该理解,只要本教导仍然可操作,步骤的顺序或执行某些动作的顺序就无关紧要。而且,可以同时进行两个或更多个步骤或动作。
如本文所用,“卤代”或“卤素”是指氟、氯、溴和碘。
如本文所用,“烷基”是指直链或支链的饱和烃基。烷基的实例包括甲基(Me),乙基(Et),丙基(例如,正丙基和z'-丙基),丁基(例如,正丁基,z'-丁基,仲丁基,叔丁基),戊基(例如,正戊基,z'-戊基,-戊基),己基等。在各种实施方案中,烷基可具有1至40个碳原子(即,C1-C40烷基),例如1-30个碳原子(即,C1-C30烷基)。在一些实施方案中,烷基可以具有1至6个碳原子,并且可以被称为“低级烷基”。低级烷基的实例包括甲基,乙基,丙基(例如,正丙基和z'-丙基)和丁基(例如,正丁基,z'-丁基,仲丁基,叔丁基)。在一些实施方案中,烷基可以如本文所述被取代。烷基通常不被另一个烷基、烯基或炔基取代。
术语“芳烷基”是本领域公认的,并且是指被芳基(例如,芳族或杂芳族基团)取代的烷基。
如本文所用,除非另有说明,“环烷基”本身或作为另一取代基是指在环系统中具有3-12个碳原子的单环烃,并且其包括氢,直链,支链和/或或环状取代基。示例性的环烷基包括环丙基、环丁基、环戊基、环己基、环庚基等。
如本文所用,“烯基”是指具有一个或多个碳-碳双键的直链或支链烷基。烯基的实例包括乙烯基,丙烯基,丁烯基,戊烯基,己烯基,丁二烯基,戊二烯基,己二烯基等。一个或多个碳-碳双键可以是内部的(例如在2-丁烯中)或末端的(例如在1-丁烯中)。在各种实施方案中,烯基可具有2至40个碳原子(即,C2-C40烯基),例如2至20个碳原子(即,C2-C20烯基)。在一些实施方案中,烯基可如本文所述被取代。烯基通常不被另一个烯基、烷基或炔基取代。
如本文所用,“稠环”或“稠环部分”是指具有至少两个环的多环系统,其中至少一个环是芳族的并且该芳族环(碳环或杂环)具有与至少一个其他可以是芳族环或非芳族环以及碳环或杂环的环共有的键。这些多环系统可以是高度p-共轭的并且任选地如本文所述被取代。
如本文所用,“杂原子”是指除碳或氢以外的任何元素的原子,并且包括例如氮,氧,硅,硫,磷和硒。
如本文所用,“芳基”是指芳族单环烃环体系或多环体系,其中两个或更多个芳族烃环稠合(即,具有共同的键)在一起或至少一个芳族单环烃环稠合到一个或多个环烷基和/或环杂烷基环上。芳基在其环系中可以具有6至24个碳原子(例如,C6-C24芳基),其可以包括多个稠合环。在一些实施方案中,多环芳基可具有8至24个碳原子。芳基的任何合适的环位置可以共价连接至限定的化学结构。仅具有芳族碳环的芳基的实例包括苯基,1-萘基(双环),2-萘基(双环),蒽基(三环),菲基(三环),稠五苯基(五环)等基团。其中至少一个芳族碳环稠合至一个或多个环烷基和/或环杂烷基环的多环体系的实例包括特别是,环戊烷的苯并衍生物(即,茚满基,其为5,6-双环环烷基/芳环体系),环己烷的苯并衍生物(即,四氢萘基,其是6,6-双环环烷基/芳环体系),咪唑啉的苯并衍生物(即苯并咪唑啉基,其是5,6-双环环杂烷基/芳环体系)和吡喃的苯并衍生物(即,色烯基,其为6,6-双环环杂烷基/芳环体系)。芳基的其他实例包括苯并二恶烷基,苯并二恶唑基,苯并二氢吡喃基,吲哚基等。在一些实施方案中,芳基可如本文所述任选地被取代。芳基环可在一个或多个位置被本文所述的此类取代基取代,例如卤素,烷基,芳烷基,烯基,炔基,环烷基,羟基,氨基,硝基,巯基,亚氨基,酰胺基,膦酸酯,次膦酸酯,羰基,羧基,甲硅烷基,醚,烷硫基,磺酰基,酮,醛,酯,杂环基,芳族或杂芳族部分,-CF3,-CN等。在一些实施方案中,芳基可以具有一个或多个卤素取代基,并且可以被称为“卤代芳基”基团。全卤代芳基,即其中所有氢原子均被卤素原子取代的芳基(例如-C6F5),包括在“卤代芳基”的定义内。在某些实施方案中,芳基被另一个芳基取代并且可以被称为联芳基。联芳基中的每个芳基可以如本文公开的被任选地取代。
如本文所用,“杂芳基”是指包含选自氧(O),氮(N),硫(S),硅(Si)和硒(Se)中的至少一个环杂原子的芳族单环体系,或其中存在于该环体系中的至少一个环是芳族的并且包含至少一个环杂原子的多环体系。多环杂芳基包括具有两个或多个稠合在一起的杂芳基的基团,以及具有至少一个稠合至一个或多个芳族碳环,非芳族碳环和/或非芳族环杂烷基环的单环杂芳基的基团。整体上,杂芳基可具有例如5至24个环原子并且含有1-5个环杂原子(即5-20元杂芳基)。杂芳基可在导致稳定结构的任何杂原子或碳原子处连接至定义的化学结构。通常,杂芳基环不包含O-O,S-S或S-O键。然而,杂芳基中的一个或多个N或S原子可被氧化(例如,吡啶N-氧化物噻吩S-氧化物,噻吩S,S-二氧化物)。杂芳基的实例包括,例如,如下所示的5或6元单环和5-6双环系统:其中T为O,S,NH,N-烷基,N-芳基,N-(芳基烷基)(例如,N-苄基),SiH2,SiH(烷基),Si(烷基)2,SiH(芳基烷基),Si(芳基烷基)2或Si(烷基)(芳基烷基)。此类杂芳基环的实例包括吡咯基,呋喃基,噻吩基,吡啶基,嘧啶基,哒嗪基,吡嗪基,三唑基,四唑基,吡唑基,咪唑基,异噻唑基,噻唑基,噻二唑基,异恶唑基,恶唑基,氧杂二唑基,吲哚基,异吲哚基,苯并呋喃基,苯并噻吩基,喹啉基,2-甲基喹啉基,异喹啉基,喹喔啉基,喹唑啉基,苯并三唑基,苯并咪唑基,苯并噻唑基,苯并异噻唑,苯并异恶唑基,苯并恶二唑,苯并恶唑基,噌啉基,1H-吲唑基,2H-吲唑基,中氮茚基,异苯并呋喃基,萘啶基,酞嗪基,蝶啶基,嘌呤基,噁唑并吡啶基,噻唑并吡啶基,咪唑并吡啶基,呋喃并吡啶基,噻吩并吡啶基,吡啶并嘧啶基,吡啶并吡嗪基,吡啶并吡嗪基,噻吩并噻唑基,噻吩并唑基,噻吩并咪唑基等。杂芳基的其他实例包括4,5,6,7-四氢吲哚基,四氢喹啉基,苯并噻吩并吡啶基,苯并呋喃基吡啶基等。在一些实施方案中,杂芳基可以任选地如本文所述的被取代。所述杂环可以在一个或多个位置被如本文所述的如下取代基取代:例如卤素,烷基,芳烷基,烯基,炔基,环烷基,羟基,氨基,硝基,巯基,亚氨基,酰胺基,膦酸酯,次膦酸酯,羰基,羧基,甲硅烷基,醚,烷硫基,磺酰基,酮,醛,酯,杂环基,芳族或杂芳族部分,-CF3,-CN等。
术语“任选地被取代”是指化学基团,例如烷基,环烷基,芳基,杂芳基等,其中一个或多个氢可以被如本文所述的取代基取代,取代基例如卤素,叠氮化物,烷基,芳烷基,烯基,炔基,环烷基,羟基,烷氧基,氨基,硝基,巯基,亚氨基,酰胺基,膦酸酯,次膦酸酯,羰基,羧基,甲硅烷基,醚,烷硫基,磺酰基,磺酰胺基,酮,醛,酯,杂环基,芳族或杂芳族部分,-CF3,-CN等。
如本文所使用的与化学基团或部分相关的表示符(representation)旨在表示上述化学基团或部分与另一化学基团或部分共价键合的共价键。
在本说明书的多个地方,以组或范围公开了化合物的取代基。专门用于指该描述包括这些基团和范围的成员的每个和每个单独的子组合。例如,术语“C1-6烷基”专门用于单独公开C1,C2,C3,C4,C5,C6,C1-C6,C1-C5,C1-C4,C1-C3,C1-C2,C2-C6,C2-C5,C2-C4,C2-C3,C3-C6,C3-C5,C3-C4,C4-C6,C4-C5和C5-C6烷基。通过其他示例,0到40范围内的整数专门用于单独公开0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39和40,以及1到20范围内的整数专门用于单独公开1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19和20。另外的例子包括短语“任选地被1-4个取代基取代”专门用于单独公开可以包括0,1,2,3,4,0-4,0-3,0-2,0-1,1-4,1-3,1-2,2-4,2-3和3-4个取代基的化学基团。
“对映异构体”是彼此为不可重叠镜像的一对立体异构体。一对相等比例的对映异构体的混合物可以称为“外消旋”混合物。在适当的时候,术语“(+/-)”用于指定外消旋混合物。可以根据Cahn-Ingold-Prelog R-S系统指定绝对立体化学。当化合物为对映异构体时,每个手性碳和/或手性轴上的立体化学均可通过R或S指定。绝对构型未知的已解析化合物可以根据其旋转平面偏振光在钠D线波长处的方向(右旋或左旋)指定为(+)或(-)。本文所述的某些化合物可包含一个或多个不对称中心和/或手性轴,因此可产生对映异构体、非对映异构体和其他立体异构体形式,其可以根据每个不对称原子或手性轴上的绝对立体化学被定义为(R)-或(S)-。本发明的化合物和方法旨在包括所有这些可能的异构体,包括基本上对映纯的形式和中间混合物。旋光的(R)-和(S)-异构体可以例如使用手性合成子或手性试剂制备,或使用常规技术拆分。
组合物的“对映体过量”或“%对映体过量”可使用以下所示的方程式计算。在下面显示的实例中,组合物包含90%的一种对映体,例如S对映体,和10%的另一种对映体,例如R对映体。ee=(90-10)/100=80%。
因此,包含90%的一种对映体和10%的另一种对映体的组合物称之为对映体过量为80%。本文所述的一些组合物包含至少约1%,约5%,约10%,约20%,约30%,约40%,约50%,约75%,约90%,约95%,约99%或更高的S对映体的对映体过量。换句话说,与R对映异构体相比,组合物包含对映异构体过量的S对映异构体。在其他实施方案中,本文所述的一些组合物包含至少约1%,约5%,约10%,约20%,约30%,约40%,约50%,约75%,约90%约95%,约99%或更高的R对映体的对映体过量。换句话说,与S对映异构体相比,组合物包含对映异构体过量的R对映异构体。
例如,在一些实施方案中,可以提供基本上不含相应对映体的对映体,并且还可以被称为“光学富集的”,“对映体富集的”,“对映体纯的”,“基本上对映纯的”和“非外消旋的”,这些术语在本文可互换使用。这些术语是指外消旋组合物的对照混合物中一种对映体的量大于一种对映体的量的组合物(例如,按重量计大于1∶1)。例如,S对映异构体的对映异构体富集制剂是指相对于制剂的总重量(例如,S和R异构体的总重量)具有大于约50重量%,例如至少约75重量%,进一步例如至少约80重量%的S对映异构体的化合物的制剂。在一些实施方案中,所述富集可以远远大于约80重量%,从而提供“基本上对映体富集的”,“基本上对映体纯的”或“基本上非外消旋的”制剂,其是指相对于制剂的总重量,具有至少约70重量%,例如至少约75重量%,例如至少约80重量%,例如至少约85重量%重量,例如至少约90重量%,和例如至少约95重量%的一种对映异构体。在某些实施方案中,本文提供的化合物由按重量计至少约90%的一种对映体组成。在其他实施方案中,该化合物由按重量计至少约95%,约98%或约99%的一种对映体组成。
在一些实施方案中,所述化合物是(S)-和(R)异构体的外消旋混合物。在其他实施方案中,本文提供化合物的混合物,其中混合物的各个化合物主要以(S)-或(R)-异构体构型存在。例如,在一些实施方案中,化合物混合物具有)大于约10%,大于约20%,大于约30%,大于约40%,大于约50%,大于约55%,大于约60%,大于约65%,大于约70%,大于约75%,大于约80%,大于约85%,大于约90%,大于约95%,大于约96%,大于约97%,大于约98%或大于约99%的(S)-对映体过量。在一些实施方案中,化合物混合物具有约55%,约60%,约65%,约70%,约75%,约80%,约85%,约90%,约95%)约96%,约97%,约98%,约99%或约99.5%或更大的(S)-对映体过量。在一些实施方案中,化合物混合物具有)约55%至约99.5%,约60%至约99.5%,约65%至约99.5%,约70%至约99.5%,约75%至约99.5%,约80%至约99.5%,约85%至约99.5%,约90%至约99.5%,约95%至约99.5%,约96%至约99.5%,约97%约99.5%,约98%至约99.5%,或约99%至约99.5%或大于约99.5%的(S)-对映体过量。
在其他实施方案中,化合物混合物具有大于约10%,大于约20%,大于约30%,大于约40%,大于约50%,大于约55%,大于约60%,大于约65%,大于约70%,大于约75%,大于约80%,大于约85%,大于约90%,大于约95%,大于约96%,大于约97%,大于约98%或大于约99%的(R)-对映体过量。在一些实施方案中,化合物混合物具有约55%,约60%,约65%,约70%,约75%,约80%,约85%,约90%,约95%,约96%,约97%,约98%,约99%或约99.5%或更大的(R)-对映体过量。在一些实施方案中,化合物混合物具有约55%至约99.5%,约60%至约99.5%,约65%至约99.5%,约70%至约99.5%,约75%至约99.5%,约80%至约99.5%,约85%至约99.5%,约90%至约99.5%,约95%至约99.5%,约96%至约99.5%,约97%约99.5%,约98%至约99.5%,或约99%至约99.5%或大于约99.5%的(R)-对映体过量。
本文提供了用于制备具有式I的四芳基甲烷的对映选择性方法:
其中Ar1、Ar2、Ar3、Ar4各自独立地为芳基或杂芳基;
所述方法包括:
在手性布朗斯特酸的存在下,在促进杂芳族亲核试剂的亲电芳香取代反应的条件下,使式II的化合物:
与杂芳族亲核试剂接触,从而形成式I的化合物。在一些实施方案中,根据本文所述的方法制备的式I的化合物是手性的,即Ar 1≠Ar 2≠Ar 3≠Ar 4的结构并且是光学富集的形式。有利地,因为亲电芳香取代反应被认为是通过三芳基甲烷碳正离子化进行的,式II的化合物可以呈外消旋或对映异构体富集的形式。
在某些实施方案中,Ar1、Ar3和Ar4选自由以下组成的组:任选取代的苯基,任选取代的呋喃基,任选取代的吡咯基,任选取代的吡唑基,任选取代的噻吩基,任选取代的吲哚基,任选取代的咪唑基,任选取代的噻唑基,任选取代的异噻唑基,任选取代的恶唑基,任选取代的异恶唑基,任选取代的苯并呋喃基,任选取代的吲哚基,任选取代的异吲哚基,任选取代的苯并噻吩基,任选取代的1,3-苯并二恶唑基,任选取代的苯并吡唑基,任选取代的苯并咪唑基,任选取代的苯并噻唑基,任选取代的苯并异噻唑基,任选取代的苯并恶唑基,任选取代的苯并异恶唑基,任选取代的萘基,取代的蒽基,任选取代的苯恶嗪基,任选取代的苯邻噻嗪基,任选取代的异喹啉基,任选取代的喹喔基,任选取代的喹唑啉基,任选取代的苯并三唑基,任选取代的苯并咪唑基,任选取代的苯并噻唑基,任选取代的苯并异噻唑基,任选取代的苯并异恶唑基,任选取代的苯并恶二唑基,噌啉基,任选取代的1H-吲唑基,任选取代的2H-吲唑基,任选取代的吲嗪基,任选取代的异苯并呋喃基,任选取代的萘啶基,任选取代的酞嗪基,任选取代的蝶啶基,任选取代的嘌呤基,任选取代的恶唑并吡啶基,任选取代的噻唑并吡啶基,任选取代的咪唑并吡啶基,任选取代的呋喃吡啶基,任选取代的噻吩并吡啶基,取代基任选取代的吡啶并嘧啶基,任选取代的吡啶并吡嗪基,任选取代噻吩并噻唑基,任选取代的噻吩并恶唑基,任选取代的吡啶,任选取代的喹啉,任选取代的嘧啶,任选取代的吡嗪,任选取代的哒嗪,任选取代的吡啶等。
在某些实施方案中,Ar1、Ar3和Ar4选自由以下组成的组:任选取代的苯基,任选取代的呋喃基,任选取代的吡咯基,任选取代的吡唑基,任选取代的噻吩基,任选取代的吲哚基,任选取代的咪唑基,任选取代的噻唑基,任选取代的异噻唑基,任选取代的恶唑基,任选取代的异恶唑基,任选取代的苯并呋喃基,任选取代的吲哚基,任选取代的异吲哚基,任选取代的苯并苯硫基,任选取代的1,3-苯并二恶唑基,任选取代的苯并吡唑基,任选取代的苯并咪唑基,任选取代的苯并噻唑基,任选取代的苯并异噻唑基,任选取代的苯并恶唑基,任选取代的苯并异恶唑基,任选取代的萘基,取代的蒽基,任选取代的吩恶嗪基和任选取代的吩噻嗪基。
在某些实施方案中,式I的四芳基甲烷具有式Ia:
其中,
m和n各自独立地选自1、2、3或4;
Ar1为芳基或杂芳基;
Ar2为杂芳基;
R1和R2各自独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,氰化物,硝基,叠氮化物,-OR3,-OSi(R3)3,-O(C=O)R3,-(C=O)OR3,-O(C=O)OR3,-(C=O)R3,-N(R4)2,-N(R4)(C=O)R3,-(C=O)N(R4)2,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-(S=O)R3,-SO2R3,-SO2N(R4)2,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)3和-(P=O)(OR3)3组成的组;或两个R1与它们所连接的碳一起形成5-6元环烷基,杂环烷基,芳基或杂芳基;或两个R2与它们所连接的碳一起形成5-6元环烷基,杂环烷基,芳基或杂芳基;
R3选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基和杂芳基组成的组;和
对于每种情况,R4独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基和杂芳基组成的组;或两个R4与它们所连接的氮一起形成3-6元杂环烷基;或一个R3和一个R4与它们所连接的原子一起形成4-6元杂环烷基;并且所述方法包括:
在手性布朗斯特酸的存在下,在促进亲电芳香取代反应的条件下,使式IIa的化合物:
与杂芳族亲核试剂接触,从而形成式Ia的化合物。不希望被理论所束缚,据信式II的化合物的反应通过三芳基甲烷碳正离子类中间体进行,该中间体在亲电芳香取代反应中与杂芳族亲核试剂反应。因此,倾向于稳定三芳基甲烷碳正离子中间体的芳基和杂芳基取代基可以提高亲电芳香取代反应的产率。同样,更富电子的杂芳族亲核试剂可以提高亲电芳香取代反应的产率。在某些实施方案中,式II化合物中的选自Ar1、Ar2和Ar3的一个、两个或三个部分包括至少一个供电子取代基。示例性的供电子取代基包括但不限于-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,-N(R4)(C=N(R4)R3,-N(R4)(C=O)N(R4)2,-N(R4)(C=N(R4))N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)3,-S(C=S)R3,-S(C=S)SR3,-N(R4)(C=S)R3,-N(R4)(C=S)N(R4)2,-N(R4)(C=S)SR3和-S(C=S)N(R4)2,其中R3选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基和杂芳基组成的组;对于每个实例,R4独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基和杂芳基组成的组;或两个R4与它们所连接的氮一起形成3-6元杂环烷基;或一个R3和一个R4与它们所连接的原子一起形成4-6元杂环烷基。
在某些实施方案中,供电子取代基共价连接至存在于式II的Ar1、Ar2和Ar3中的一个或多个的芳环中的至少一个原子,其与三芳基甲烷碳正离子中间体π共轭。例如,当Ar3是任选取代的苯基部分时,当供电子取代基共价连接至选自如下图所示的苯基部分的邻位和对位的至少一个位置上时:
它与三芳基甲烷碳正离子中间体π共轭。
在这样的实施方案中,式IIa的化合物可以由选自以下的结构表示:
其中,m为0、1、2或3;
n为1、2、3或4;
p为0、1、2或3;
q为0、1或2;
Ar1选自由以下组成的组:
X为NR11、O、S或Se;
R1和R2各自独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,氰化物,硝基,叠氮化物,-OR3,-OSi(R3)3,-O(C=O)R3,-(C=O)OR3,-O(C=O)OR3,-(C=O)R3,-N(R4)2,-N(R4)(C=O)R3,-(C=O)N(R4)2,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-(S=O)R3,-SO2R3,-SO2N(R4)2,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)3和-(P=O)(OR3)3组成的组;或两个R1与它们所连接的碳一起形成5-6元环烷基,杂环烷基,芳基或杂芳基;或R2的两个实例与它们所连接的碳一起形成5-6元环烷基,杂环烷基,芳基或杂芳基;
R1’选自由-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,
-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;R1’和一个R1与它们所连接的碳一起形成5-6元环烷基,杂环烷基,芳基或杂芳基;
每个R9独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,氰化物,硝基,叠氮化物,-OR3,-OSi(R3)3,-O(C=O)R3,-(C=O)OR3,-O(C=O)OR3,-(C=O)R3,-N(R4)2,-N(R4)(C=O)R3,-(C=O)N(R4)2,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-(S=O)R3,-SO2R3,-SO2N(R4)2,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)3和-(P=O)(OR3)3组成的组;
R9’选自由-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,
-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;或两个R9’与它们所连接的碳一起形成5-6元环烷基,杂环烷基,芳基或杂芳基;且
R10选自由烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3或-SeR3组成的组;且
R11为氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,-(C=O)OR3,-(C=O)R3,-(C=O)N(R4)2,-SO2R3或-SO2N(R4)2。
杂芳族亲核试剂可以是由式IV表示的化合物:
其中,t为0、1、2或3;
Y为NR13、O、S或Se;
每个R12独立地选自由氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物,氰化物,硝基,叠氮化物,-OR3,-OSi(R3)3,-O(C=O)R3,-(C=O)OR3,-O(C=O)OR3,-(C=O)R3,-N(R4)2,-N(R4)(C=O)R3,-(C=O)N(R4)2,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-(S=O)R3,-SO2R3,-SO2N(R4)2,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)3和-(P=O)(OR3)3组成的组;或两个R12与它们所连接的碳一起形成5-6元环烷基,亚环烷基,杂环烷基,芳基或杂芳基;和
R13为氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基,-(C=O)OR3,-(C=O)R3,-(C=O)N(R4)2,-SO2R3或-SO2N(R4)2。
在某些实施方案中,t为1或2;Y为NH;R12为氢,烷基,卤代烷基,全卤代烷基,烯烃,炔烃,环烷基,杂环烷基,芳基,芳烷基,杂芳基;或两个R12与它们所连接的碳一起形成5-6元环烷基或亚环烷基。
在某些实施方案中,杂芳族亲核试剂选自由以下组成的组:任选取代的吡咯,任选取代的2-烷基吡咯,任选取代的3-烷基吡咯,任选取代的2-芳基吡咯,任选取代的3-芳基吡咯,任选取代的四氢-1H-吲哚,任选取代的4,7-二氢-1H-吲哚,任选取代的呋喃,任选取代的噻吩,任选取代的硒酚,任选取代的苯并噻吩,任选取代的苯,任选取代的苯酚,任选取代的萘酚和任选取代的苯硫酚。
通常,相对于式II的化合物,可以使用一个或多个当量的杂芳族亲核试剂。然而,在杂芳族亲核试剂昂贵或仅少量可获得的情况下,可以过量使用式II的化合物。在某些实施方案中,关于式II的化合物,使用1至10、1至7、1至5、1至4、1至3、1至2或1至1.5或1至1.1当量。
在本文描述的方法中使用的手性布朗斯特酸可以是任何手性布朗斯特酸。手性布朗斯特酸的选择完全在本领域技术人员的技术范围内,并且通常取决于所需产物的结构以及目标产率和ee。图2中描述的实验结果显示了在本文描述的方法中筛选不同手性布朗斯特酸的结果。可以通过筛选与结构相关的手性布朗斯特酸来进一步提高收率和/或ee,从而优化所观察到的手性布朗斯特酸的ee和收率。例如,当测试与结构相关的类似物条目4时,条目3的产率和ee得到改善。
在某些实施方案中,手性布朗斯特酸是手性磷酸。手性磷酸可以是C2对称的手性磷酸。在某些实施方案中,手性磷酸由式IIIa、式IIIb、式IIIc或式IIId表示:
其中Q为O、S或NSO2R16;
Z为O、S或Se;
R5和R5’各自独立地为氢,烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三芳基硅烷;
R6和R6’各自独立地为氢,烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三烷基硅烷;
R7和R7’各自独立地为烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三烷基硅烷;或R6'和R7’与它们所连接的碳一起形成5-6元环烷基或6元芳基,R6和R7与它们所相连的碳一起形成5-6元环烷基或6元芳基;
R14和R14’各自独立地为氢,烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三烷基硅烷;
R15和R15’各自独立地为氢,烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三烷基硅烷;并且
R16为烷基或芳基。
在某些实施方案中,手性磷酸由式IIIa或式IIIb表示:
其中Q是O;
Z是O;
R5和R5’各自独立地为氢,烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三芳基硅烷;
R6和R6’各自独立地为氢,烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三烷基硅烷;并且
R7和R7’各自独立地为烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,卤化物或三烷基硅烷;或R6’和R7’与它们所连接的碳一起形成5-6元环烷基或6元芳基,且R6和R7与它们所相连的碳一起形成5-6元环烷基或6元芳基。
在某些实施方案中,手性磷酸具有以下结构:
其中
p为1、2、3或4;且
R8为氢,烷基,卤代烷基,全卤代烷基,环烷基,杂环烷基,芳基,卤化物和三芳基硅烷。
在某些实施方案中,手性磷酸具有以下结构:
其中
p是1、2、3或4;和
R8是烷基,环烷基或芳基。
手性布朗斯特酸通常是光学富集的。在某些实施方案中,手性布朗斯特酸的ee为50%或更大,60%或更大,70%或更大,80%或更大,90%或更大,95%或更大,97%或更大,98%或更大,99%或更大。在某些实施方案中,手性布朗斯特酸的ee为90%至99.9%,95%至99.9%或98%至99.9%。
式IIIa或式IIIb的各种手性磷酸的产率和ee显示在图3和图7中。在所有情况下,式1的化合物的ee为良好至优异。
相对于式II的化合物,手性布朗斯特酸可以以0.5至20摩尔%存在于反应中。在某些实施方案中,相对于式II的化合物,手性布朗斯特酸以0.5至15摩尔%,1至15摩尔%,2.5至15摩尔%,5至15摩尔%或5至10摩尔%存在于反应中。
非极性和极性非质子溶剂可用于本文所述的方法。在某些实施方案中,所述溶剂选自芳族溶剂,卤代芳族溶剂,醚,酮,卤代烷烃,全卤代烷烃及其组合。示例性的溶剂包括但不限于苯,甲苯,氯苯,三氟甲基苯,乙醚,二甲氧基乙烷,四氢呋喃,四氢吡喃,二恶烷,叔丁基甲基醚,二氯甲烷,氯仿,1,2-二氯乙烷,四氯化碳及其组合。图4和图8显示,在卤代烷溶剂(例如二氯甲烷和1,2-二氯乙烷)中,可以获得高收率和ee。
取决于式II化合物的结构、杂芳族亲核试剂和所需的ee/收率,进行本文所述方法的最佳温度可以是高于-60℃的任何反应温度。在某些实施方案中,反应温度为-40℃至60℃,-40℃至50℃,-30℃至50℃,-30℃至40℃,-20℃至40℃,-20℃和30℃,-20℃和25℃,-10℃和25℃,-10℃和22℃或0℃和22℃之间。在某些实施方案中,反应温度为22℃或更低。
图11和12中的实验结果证明了在式II的化合物上被耐受的在结构和电子上不同的取代基的广泛范围,并且以优异的收率和ee提供了式I的化合物。取决于用于催化亲电芳香取代反应的手性布朗斯特酸的对映异构体,可以选择性地获得式I化合物的(R)或(S)对映异构体。可以以10%至99.9%的对映体过量(ee)来制备式I的化合物。在某些实施方案中,式I的化合物的ee为20%至99.9%,30%至99.9%,40%至99.9%,40%至99.5%,40%至98%,50%至98%,60%至98%,70%至98%,75%至98%,80%至98%,80%至96%,85%至98%,90%至98%或90%至97%。在某些实施方案中,式I化合物的ee大于40%,大于50%,大于60%,大于70%,大于80%,大于90%,大于95%或大于97%。
本文所述的方法能够以30%至98%或甚至更高的产率制备式I的化合物。如图2-11中所示的筛选数据所证明的,可以使用本领域公知的常规方法进一步优化本文所述的方法以增加式I的特定化合物的收率和ee。
根据本文所述方法制备的式I化合物的ee可以任选地使用本领域已知的任何方法来提高,例如通过重结晶,手性色谱法或非对映体的形成以及使用常规分析技术(例如,柱色谱,结晶等)进行的分离。
本文所述的方法也可以用外消旋或非手性布朗斯特酸进行。在这种情况下,式I化合物将以外消旋形式制备。
本文所述的方法提供了制备多种式I的手性四芳基甲烷的有效手段。这些化合物可以通过使用直接的合成反应,例如烷基化、氧化和溴化,任选地转化为其他有用的化合物。对映异构体过量的式I化合物通常可以保持完整,而不会被随后的合成步骤侵蚀。
实施例
快速柱色谱法在购自中国青岛谱科公司的硅胶(200-300目)上进行。所有对空气或湿气敏感的反应均在氮气气氛下使用无水溶剂在烘箱干燥的玻璃器皿中进行。通过溶剂纯化系统纯化无水溶剂。除非另有说明,否则化学药品是从商业供应商处购买的,无需进一步纯化即可使用。在Bruker AV 400MHz NMR光谱仪上收集1H、13C、19F和31PNMR光谱,使用残留溶剂峰作为内标(1H NMR:丙酮-d6在2.05ppm;13C NMR:丙酮-d6在29.84ppm)。1H NMR的数据记录如下:化学位移(δ,ppm),多重性(s=单峰;d=双峰;t=三重峰;q=四重峰;p=五重峰;sept=七重峰;m=多重峰;br=宽峰),耦合常数(Hz),积分面积。在Agilent GC/MS 5975C系统,MALDI Micro MX质谱仪或API QSTAR XL系统上收集质谱。在Bruker TENSOR 27光谱仪上记录IR光谱,并以吸收频率(cm-1)报告。在JASCO P-2000旋光仪上测量旋光度,以度表示[α]D值;浓度(c)为10mg/mL。使用Agilent 1200LC仪器和DaicelAD-H、IC-H、AS-H或OD-H色谱柱,通过手性HPLC测定对映体过量值。
通用步骤:向三芳基甲醇II(0.2mmol)和杂环芳烃(III)(0.2-0.4mmol)在DCE(3.6mL)中的混合物中,加入在DCE(0.4mL)中的催化剂(R)-BINOL-2,4,6-Cy3C6H2-OH(5-15摩尔%),然后在特定温度下搅拌48小时。通过薄层色谱监测进展。完成后(每种情况指定时间),将混合物直接进行硅胶快速色谱法,得到纯的产物。
(R)-4-((2-甲氧基苯基)(5-甲基-1H-吡咯-2-基)(苯基)甲基)苯酚(Ia)由4-(羟基(2-甲氧基苯基)(苯基)甲基)苯酚(61.2mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)根据通用步骤制备(洗脱液:己烷/乙酸乙酯=15:1至10:1),为无色油,产率为97%(71.7mg,96%ee)。
[α]D 26:+6.9(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK IC柱;含有3%i-PrOH(异丙醇)的己烷;1.0mL/min;保留时间:9.7分钟(主要),11.1分钟(次要)。
1H NMR(400MHz,丙酮-d6)δ8.78(s,1H),8.22(s,1H),7.29–7.25(m,1H),7.22–7.12(m,5H),7.00–6.85(m,5H),6.71(d,J=8.7Hz,2H),5.70–5.63(m,1H),5.58–5.60(m,1H),3.17(s,3H),2.13(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.8,156.0,146.9,137.6,136.6,136.5,132.1,130.8,130.5,129.1,127.8,127.5,126.2,121.0,114.4,114.0,110.4,105.3,59.1,55.5,13.1。
IR(薄膜)3446,3384,3056,2983,2839,1588,1247,1039,733,700cm-1。
HRMS(CI+)计算值C25H23NO2(M+):369.1729,实测值:369.1725。
(R)-4-(苯并[d][1,3]二氧杂环戊烷-4-基(5-甲基-1H-吡咯-2-基)(苯基)甲基)苯酚(Ib)由4-(苯并[d][1,3]二氧杂环戊烷-4-基(羟基)(苯基)甲基)-苯酚(64.0mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)根据通用步骤制备(洗脱液:己烷/乙酸乙酯=15:1至10:1),为无色油,产率为94%(72.1mg,78%ee)。
[α]D 26:+4.5(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有3%i-PrOH的己烷;1.0mL/min;保留时间:38.9分钟(主要),40.8分钟(次要)。
1H NMR(400MHz,丙酮-d6)δ9.08(s,1H),8.30(s,1H),7.26–7.13(m,5H),6.94(d,J=8.4Hz,2H),6.81(d,J=8.4Hz,1H),6.77–6.71(m,3H),6.55(d,J=8.0,1H),5.72–5.59(m,4H),2.16(s,3H)。
13C NMR(100MHz,丙酮-d6)δ156.5,148.6,146.3,146.1,136.3,135.0,131.9,131.2,130.7,128.1,128.0,126.9,123.5,121.8,114.8,110.7,108.3,105.45,100.8,58.2,13.1。
IR(薄膜)3440,3416,3052,2975,2885,1589,1440,1259,733cm-1。
HRMS(LD+)计算值C25H21NO3(M+):383.1521,实测值:383.1519。
(R)-2-((4-羟基苯基)(5-甲基-1H-吡咯-2-基)(苯基)甲基)苯酚(Ic)由2-(羟基(4-羟基苯基)(苯基)甲基)苯酚(58.4mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)根据通用步骤(在-20℃下)制备(洗脱液:己烷/乙酸乙酯=15∶1至10∶1),为无色油,产率为94%(66.6mg,88%ee)。
[α]D 26:+4.3(c=1.0,氯仿。产物的HPLC分析:Daicel CHIRALPAK IC-H柱;含有5%的i-PrOH的己烷;1.0mL/min;保留时间:7.5分钟(次要),9.6分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.39(s,1H),8.34(br,1H),7.27–7.12(m,6H),6.94(d,J=8.4Hz,2H),6.86(d,J=7.7Hz,1H),6.79–6.73(m,4H),6.39(br,1H),5.87–5.80(m,1H),5.77–5.71(m,1H),2.17(s,3H)。
13C NMR(100MHz,丙酮-d6)δ156.7,156.6,146.4,136.5,134.3,133.3,132.2,131.1,130.9,130.0,129.4,128.1,127.0,120.1,117.8,115.0,110.7,105.8,58.4,13.1。
IR(薄膜)3427,3387,3054,2981,2862,1603,1261,1210,1179,737,700cm-1。
HRMS(CI+)计算值C24H21NO2(M+):355.1572,实测值:355.1581。
(R)-N-(2-((4-羟基苯基)(5-甲基-1H-吡咯-2-基)(苯基)甲基)-苯基)萘-1-磺酰胺(Id)由N-(2-(羟基(4-羟基苯基)(苯基)甲基)苯基)萘-1-磺酰胺(96.2mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)根据通用步骤(在室温下使用15mol%的催化剂(29.8mg,0.03mmol)DCM作为溶剂)制备(洗脱液:己烷/乙酸乙酯=15:1至10:1),为无色油,产率为85%(92.9mg,95%ee)。
[α]D 26:+4.5(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK IC柱;含有30%i-PrOH的己烷;1.0mL/min;保留时间:12.4分钟(主要),15.1分钟(次要)。
1H NMR(400MHz,丙酮-d6)δ9.42(s,1H),8.50(s,1H),8.24(d,J=7.3Hz,1H),8.19(d,J=8.2Hz,1H),8.07–7.98(m,2H),7.67–7.61(m,3H,),7.46(s,1H),7.30–7.24(m,3H),7.15–7.09(m,4H),6.93–6.88(m,4H),6.74(d,J=8.5Hz,2H),6.19-6.11(m,1H),6.00-5.94(m,1H),2.13(s,3H)。
13C NMR(100MHz,丙酮-d6)δ156.9,145.9,138.9,138.2,136.2,135.2,135.1,134.5,133.3,132.2,131.7,131.2,130.9,129.7,129.3,129.1,128.7,128.6,128.4,127.7,127.4,125.3,125.2,123.2,118.9,115.3,111.0,106.4,59.0,13.2。
IR(薄膜)3435,3376,3057,2925,2851,1589,1264,743,700cm-1。
HRMS(LD+)计算值C34H28N2O3S(M+):544.1821,实测值:544.1840。
(R)-4-((2-(丁硫基)苯基)(5-甲基-1H-吡咯-2-基)(苯基)甲基)苯酚(Ie)由4-((2-(丁硫基)苯基)(羟基)(苯基)甲基)苯酚(72.8mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)根据通用步骤(在室温下)制备(洗脱液:己烷/乙酸乙酯=15:1至10:1),为无色油,产率为90%(76.5mg,81%ee)。
[α]D 26:+7.1(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK IC柱;含有3%i-PrOH的己烷;1.0mL/min;保留时间:8.3分钟(主要),9.7分钟(次要)。
1H NMR(400MHz,丙酮-d6)δ8.74(s,1H),8.28(s,1H),7.46(d,J=7.5Hz,1H),7.26–7.16(m,6H),7.11(t,J=7.8Hz,1H),6.99–6.94(m,3H),6.71(d,J=8.6Hz,2H),5.68–5.64(m,1H),5.61–5.56(m,1H),2.37(t,J=6.9Hz,2H),2.13(s,3H),1.22–1.10(m,4H),0.76(t,J=6.9Hz,3H)。
13C NMR(100MHz,丙酮-d6)δ156.3,148.5,146.2,140.7,136.5,136.2,132.9,132.6,131.4,131.2,128.2,128.0,127.7,126.5,126.1,114.6,111.1,105.6,61.0,35.6,31.5,22.7,13.9,13.1。
IR(薄膜)3444,3386,3052,2957,2927,2865,1587,1262,1175,735,700cm-1。HRMS(LD+)计算值C28H29NOS(M+):427.1970,实测值:427.1982。
(R)-4-((2-氟-4-甲氧基苯基)(5-甲基-1H-吡咯-2-基)(苯基)甲基)苯酚(If)由4-((2-氟-4-甲氧基苯基)(羟基)(苯基)甲基)苯酚(64.8mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)根据通用步骤制备(洗脱剂:己烷/乙酸乙酯=15∶1至10∶1),为无色油,产率93%(80.6mg,91%ee)。
[α]D 26:+1.5(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK OD-H柱;含有5%iPrOH的己烷;1.0mL/min;保留时间:19.1分钟(主要),24.2分钟(次要)。
1H NMR(400MHz,丙酮-d6)δ8.97(s,1H),8.31(s,1H),7.27–7.16(m,5H),6.96–6.91(m,3H),6.74(d,J=8.8Hz,2H),6.67(dd,J1=12.9,J2=2.6Hz,1H),6.61(dd,J1=12.9,J2=2.7Hz,1H),5.68–5.65(m,2H),3.79(s,3H),2.15(m,3H)。
13C NMR(100MHz,丙酮-d6)δ163.3(d,J=247.6Hz),162.1(d,J=11.0Hz),156.5,146.5,136.5,135.3,131.8(d,J=5.7Hz),131.7,130.3,128.3,128.0,127.9(d,J=11.3Hz),126.8,114.9,110.3,109.4(d,J=2.6Hz),105.5,103.0(d,J=26.5Hz),57.8,55.8,13.1。
19F NMR(376MHz,丙酮-d6)δ-97.8。
IR(薄膜)3446,3054,2932,1616,1261,824,733cm-1。
HRMS(CI+)计算值C25H22FNO2(M+):387.1635,实测值:387.1624。
(S)-4-((4-氟苯基)(2-甲氧基苯基)(5-甲基-1H-吡咯-2-基)甲基)苯酚(Ig)由4-((4-氟苯基)(羟基)(2-甲氧基苯基)甲基)苯酚(62.8mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)根据通用步骤制备(洗脱液:己烷/乙酸乙酯=15∶1至10∶1),为无色油,产率93%(72.1mg,92%ee)。
[α]D 26:+6.9(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK IC-H柱;含有3%i-PrOH的己烷;1.0mL/min;保留时间:8.7分钟(主要),9.8分钟(次要)。
1H NMR(400MHz,丙酮-d6)δ8.84(s,1H),8.27(s,1H),7.30–7.25(m,1H),7.18–7.14(m,2H),7.00–6.90(m,6H),6.88(td,J1=7.6,J2=1.0Hz,1H),6.72(d,J=8.8Hz,2H),5.66(t,J=2.4Hz,1H),5.58(t,J=3.0Hz,1H),3.21(s,3H),2.13(s,3H)。
13C NMR(100MHz,丙酮-d6)δ161.6(d,J=240.1Hz),158.7,156.1,142.8(d,J=3.3Hz),137.4,136.4,132.2(d,J=6.7Hz),131.9,130.7,129.3,128.0,121.0,114.5,114.0(d,J=21.0Hz),113.8,110.4,105.4,58.5,55.4,13.1。
19F NMR(376MHz,丙酮-d6)δ-118.1。
IR(薄膜)3447,3053,2980,2936,1593,1476,1261,1020,733cm-1。
HRMS(CI+)计算值C25H22NFO2(M+):387.1635,实测值:387.1638。
(S)-4-((2-甲氧基苯基)(4-甲氧基苯基)(5-甲基-1H-吡咯-2-基)甲基)苯酚(Ih)由4-(羟基(2-甲氧基苯基)(4-甲氧基苯基)甲基)苯酚(67.2mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)根据通用步骤(使用15mol%的催化剂(在室温下)制备(洗脱液:己烷/乙酸乙酯=15∶1至10∶1),为无色油,产率为94%(74.7mg,83%ee)。
[α]D 26:+1.7(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK IC-H柱;含有5%i-PrOH的己烷;1.0mL/min;保留时间:8.7分钟(主要),10.1分钟(次要)。
1H NMR(400MHz,丙酮-d6)δ8.76(s,1H),8.19(s,1H),7.26(t,J=7.9Hz,1H),7.04(d,J=8.4Hz,2H),6.92–6.92(m,4H),6.86(t,J=7.4Hz,1H),6.77(d,J=8.7Hz,2H),6.69(d,J=8.2Hz,2H),5.68–5.61(m,1H),5.68–5.54(m,1H),3.75(s,3H),3.20(s,3H),2.13(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.9,158.4,155.9,138.7,137.9,137.3,136.9,131.8,131.7,130.7,129.1,127.6,121.0,114.4,114.0,112.8,110.2,105.3,58.4,55.6,55.3,13.1。
IR(薄膜)3445,3389,3050,2838,1590,1249,1176,1031,821,735cm-1。
HRMS(LD+)计算值C26H25NO3(M+):399.1834,实测值:399.1827。
(S)-4-((2-甲氧基苯基)(5-甲基-1H-吡咯-2-基)(萘-2-基)甲基)苯酚(Ii).由4-(羟基(2-甲氧基苯基)(萘-2-基)甲基)苯酚(71.2mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)根据通用步骤制备(洗脱液:己烷/乙酸乙酯=15∶1至10∶1),为无色油,产率为92%(88.7mg,93%ee)。
[α]D 26:+11.8(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK IC-H柱;含有3%i-PrOH的己烷;1.0mL/min;保留时间:11.7分钟(主要),13.3分钟(次要)。
1H NMR(400MHz,丙酮-d6)δ8.90(s,1H),8.25(s,1H),7.83(d,J=7.3Hz,1H),7.72–7.64(m,3H),7.45–7.28(m,4H),7.09–7.03(m,3H),6.96–6.89(m,2H),6.74(d,J=8.6Hz,2H),5.73–5.65(m,2H),3.16(s,3H),2.13(s,3H)。
13C NMR(100MHz,丙酮-d6)δ159.0,156.1,144.0,137.4,136.9,136.3,133.9,132.8,132.0,130.9,130.4,129.3,128.9,128.4,128.0,128.0,126.4,126.31,126.22,121.1,114.5,114.0,110.5,105.5,59.2,55.5,13.1。
IR(薄膜)3441,3380,3052,2836,1588,1243,734,698cm-1。
HRMS(LD+)计算值C29H25NO2(M+):419.1885,实测值:419.1883。
(R)-4-((2-甲氧基苯基)(5-甲基-1H-吡咯-2-基)(噻吩-3-基)甲基)苯酚(Ij)由4-(羟基(2-甲氧基苯基)(噻吩-3-基)甲基)苯酚(62.4mg,0.2mmol)和2-甲基吡咯(32.4mg,0.4mmol)根据通用步骤(在40℃)制备(洗脱液:己烷/乙酸乙酯=15:1至10:1),为无色油,收率为87%(65.5mg,87%ee)。
[α]D 26:+10.3(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有5%i-PrOH的己烷;1.0mL/min;保留时间:12.9分钟(主要),14.8分钟(次要)。
1H NMR(400MHz,丙酮-d6)δ8.87(s,1H),8.20(s,1H),7.29–7.24(m,2H),6.97–6.92(m,3H),6.86–6.81(m,3H),6.78(d,J=5.0Hz,1H),6.69(d,J=8.6Hz,2H),5.66–5.61(m,1H),5.55(t,J=2.9Hz,1H),3.27(s,3H),2.14(s,3H)。
13C NMR(100MHz,丙酮-d6)δ159.0,156.1,148.2,137.6,137.6,135.9,131.3,131.0,130.4,129.2,127.5,123.8,123.3,121.0,114.6,114.1,109.7,105.5,56.1,55.7,13.1。
IR(薄膜)3443,3393,3049,2837,1587,1251,1175,733,703cm-1。
HRMS(LD+)计算值C23H21NO2S(M+):375.1298,实测值:375.1311。
(R)-4-((2-甲氧基苯基)(苯基)(4,5,6,7-四氢-1H-吲哚-2-基)甲基)苯酚(Ik)由4-(羟基(2-甲氧基苯基)(苯基)甲基)苯酚(61.2mg,0.2mmol)和4,5,6,7-四氢-1H-吲哚(48.4mg,0.4mmol)根据通用步骤制备(洗脱液:己烷/乙酸乙酯=15∶1至10∶1),为无色油,产率为92%(75.1mg,83%ee)。
[α]D 26:+0.8(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK IC-H柱;含有3%i-PrOH的己烷;1.0mL/min;保留时间:8.3分钟(主要),9.3分钟(次要)。
1H NMR(400MHz,丙酮-d6)δ8.47(s,1H),8.23(s,1H),7.28–7.21(m,6H),7.03–6.85(m,5H),6.70(d,J=8.2Hz,2H),5.46(s,1H),3.16(s,3H),2.45(t,J=5.9Hz,2H),2.40(t,J=5.7Hz,2H),1.72–1.69(m,4H)。
13C NMR(100MHz,丙酮-d6)δ158.9,156.0,146.9,137.9,136.6,136.1,132.1,130.8,130.5,129.1,127.5,127.0,126.1,121.0,115.5,114.4,114.0,109.7,59.1,55.5,24.8,24.3,23.7,23.4。
IR(薄膜)3447,3402,3054,2844,1598,1241,1174,733,700cm-1。
HRMS(LD+)计算值C28H27NO2(M+):409.2042,实测值:409.2054。
(R)-4-((2-甲氧基苯基)(苯基)(5-苯基-1H-吡咯-2-基)甲基)苯酚(Il)由4-(羟基(2-甲氧基苯基)(苯基)甲基)苯酚(61.2mg,0.2mmol)和2-苯基吡咯(57.2mg,0.4mmol)根据通用步骤制备(洗脱液:己烷/乙酸乙酯=15:1至10:1),为无色油,产率为98%(84.9mg,ee为81%)。
[α]D 26:+8.8(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK OD-H柱;含有5%i-PrOH的己烷;1.0mL/min;保留时间:11.2分钟(次要),12.2分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.50(s,1H),8.32(s,1H),7.49(d,J=7.8Hz,2H),7.32–7.19(m,8H),7.13–7.07(m,2H),7.02–7.00(m,3H),6.90(t,J=7.6Hz,1H),6.77(d,J=8.6Hz,2H),6.46(t,J=2.9Hz,1H),5.86(t,J=2.8Hz,1H),3.25(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.8,156.2,146.7,139.8,136.9,136.4,134.1,132.3,132.1,131.0,130.5,129.4,129.3,127.7,126.5,126.1,124.2,121.2,114.6,114.3,112.6,105.8,59.3,55.7。
IR(薄膜)3449,3366,3054,2836,1600,1254,732,697cm-1。
HRMS(LD+)计算值C30H25NO2(M+):431.1885,实测值:431.1876。
(R)-4-((2-甲氧基苯基)(苯基)(1H-吡咯-2-基)甲基)苯酚(Im)由4-(羟基(2-甲氧基苯基)(苯基)甲基)苯酚(61.2mg,0.2mmol)和吡咯(67.0mg,1.0mmol,5当量)根据通用步骤制备(洗脱液:己烷/乙酸乙酯=15∶1至10∶1),为无色油,产率为94%(66.8mg,>99%ee)。
[α]D 26:+3.6(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK IC-H柱;含有2%i-PrOH的己烷;1.0mL/min;保留时间:12.8分钟(主要>99%)。
1H NMR(400MHz,丙酮-d6)δ9.06(s,1H),8.26(s,1H),7.30–7.13(m,6H),6.96–6.85(m,5H),6.72–6.68(m,3H),6.03–5.93(m,1H),5.82–5.71(m,1H),3.19(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.9,156.1,146.9,137.9,137.4,136.7,132.0,130.7,130.5,129.3,127.6,126.3,121.0,118.1,114.5,114.0,110.2,107.3,59.1,55.5。
IR(薄膜)3447,3055,2835,1598,1241,1176,731cm-1。
HRMS(LD+)计算值C24H21NO2(M+):355.1572,实测值:355.1556。
(R)-4-((4,7-二氢-1H-吲哚-2-基)(2-甲氧基苯基)(苯基)甲基)苯酚(In)由4-(羟基(2-甲氧基苯基)(苯基)甲基)苯酚(61.2mg,0.2mmol)和4,7-二氢-1H-吲哚(47.6mg,0.4mmol,2当量)根据通用步骤制备(洗脱剂:己烷/乙酸乙酯=15∶1至10∶1),为无色泡沫固体,产率为86%(70.4mg,86%ee)。
[α]D 26:+2.2(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK IC-H柱;含有3%i-PrOH的己烷;1.0mL/min;保留时间:9.0分钟(次要),10.7分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ8.66(s,1H),8.21(s,1H),7.29–7.14(m,6H),7.02–6.86(m,5H),6.72–6.69(m,2H),5.85-5.82(m,1H),5.79-5.76(m,1H),5.53–5.52(m,1H),3.15–3.10(m,4H),3.17(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.9,156.1,146.9,137.7,137.0,136.6,132.1,130.8,130.5,129.2,127.6,126.5,126.2,124.32,124.27,121.0,114.4,114.0,112.7,108.9,59.2,55.5,25.6,24.7。
IR(薄膜)3447,3405,2831,1696,1599,1255,1175,1108,820,731cm-1。
HRMS(CI+)计算值C28H25NO2(M+):407.1885,实测值:407.1888。
(R)-2-((2-甲氧基苯基)(4-甲氧基苯基)(苯基)甲基)-1H-吲哚(Io)。在室温下,向In(61.1mg,0.15mmol,1.0当量)在丙酮(4mL)中的溶液中依次加入MeI(64.4mg,0.45mmol,3.0当量)和K2CO3(104mg,0.75mmol,5.0当量)。将反应混合物在室温下搅拌24h,并通过硅胶短垫过滤,将其用Et2O洗涤。将滤液在减压下浓缩,并将粗产物溶解在无水DCM(8mL)中。一次性加入DDQ(38mg,0.175mmol,1.1当量)。反应混合物在室温下搅拌3小时。反应混合物用DCM(15mL)稀释,然后用NaOH溶液的水溶液(15mL,10%wt.)和水(2×15mL)洗涤,并用Na2SO4干燥。之后,将反应混合物在减压下浓缩并通过硅胶色谱法纯化,分两步得到目标产物(洗脱液:己烷/乙酸乙酯=15:1至10:1),产率为81%(51.2mg,86%ee)。
[α]D 26:-1.5(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK OD-H柱;含有3%i-PrOH的己烷;1.0mL/min;保留时间:10.3分钟(次要),11.1分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.46(s,1H),7.46(d,J=7.7Hz,1H),7.28–7.18(m,6H),7.09(d,J=8.9Hz,2H),7.03–6.88(m,5H),6.82(d,J=8.9Hz,2H),6.34(s,1H),3.77(s,3H),3.20(s,3H)。
13C NMR(100MHz,丙酮-d6)δ159.0,158.8,146.0,145.5,137.7,137.2,136.1,132.2,130.81,130.75,129.7,128.7,127.9,126.7,121.7,121.2,120.7,119.8,114.0,113.2,111.8,104.3,59.6,55.5,55.4。
IR(薄膜)3448,3053,2836,1592,1290,1105,799,731cm-1。
HRMS(CI+)计算值C29H25NO2(M)+:419.1885,实测值:419.1886。
在室温下,向装有叔醇4(0.2mmol)和吡咯2(0.4mmol)在DCE(0.8mL)中的溶液的烘干的4-mL小瓶中缓慢加入催化剂(R)-BINOL-2,4,6-Cy3C6H2-OH(14.9mg,0.015mmol,7.5mol%)在DCE(0.2mL)中的溶液。将反应混合物在相同温度下搅拌24小时。接下来,加入Na2CO3(212mg,2.0mmol)。将混合物搅拌10分钟并在减压下浓缩。残余物通过硅胶色谱纯化,得到目标产物。
(S)-2-((2-甲氧基苯基)(苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5a)由4-(羟基(2-甲氧基苯基)(苯基)甲基)苯酚(81.3mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E制备(洗脱液:己烷/乙酸乙酯=20:1→15:1),为白色泡沫,产率为96%(87.0mg,96%ee)。
[α]D 26:+0.5(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有5%的i-PrOH的己烷;1.0mL/min;保留时间:8.1分钟(次要),18.0分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.42(s,1H),9.32(s,1H),7.41(d,J=8.1Hz,1H),7.26(d,J=8.0Hz,1H),7.24–7.06(m,7H),7.02–6.86(m,7H),6.78(td,J1=7.6Hz,J2=1.2Hz,1H),6.70(dd,J1=8.2Hz,J2=1.2Hz,1H),6.64(td,J1=2.7Hz,J2=1.6Hz,1H),5.98(dt,J1=3.5Hz,J2=2.6Hz,1H),5.84(ddd,J1=3.4Hz,J2=2.7Hz,J3=1.6Hz,1H),3.19(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.6,145.0,137.6,136.7,135.5,135.4,135.0,131.2,130.9(2C),130.6,129.6,127.7,127.5,126.8,125.7,122.1,120.7,119.8,119.6,118.1,116.3,113.4,111.8,110.4,107.8,56.1,55.5。
IR(薄膜)3412,3055,3008,2935,1591,1543,1245,1089,1022,1089,1022,801,745,702cm-1。
HRMS(LD+)计算值C32H26N2O(M+):454.2045,实测值:454.2052。
(S)-2-((2-(苄氧基)苯基)(苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5b)由(2-(苄氧基)苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇(96.2mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E制备(洗脱剂:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为81%(85.8mg,91%ee)。
[α]D 26:-2.2(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:5.5分钟(次要),9.0分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.42(s,1H),9.35(s,1H),7.37(dd,J1=8.1Hz,J2=2.1Hz,1H),7.25–7.23(m,3H),7.19–6.92(m,13H),6.89–6.81(m,2H),6.83–6.66(m,4H),6.63–6.54(m,1H),5.96–5.94(m,1H),5.83–5.81(m,1H),4.72(d,J=12.0Hz,1H),4.57(d,J=12.1Hz,1H)。
13C NMR(100MHz,丙酮-d6)δ157.5,144.8,137.8,137.5,136.7,135.6,135.5,134.5 131.3,131.2,131.0,130.9,129.6,128.6,127.9,127.8,127.6,126.9,125.8,122.2,120.8,119.9,119.6,118.2,116.2,113.6,111.9,110.6,107.9,107.8 70.2,56.3。
IR(薄膜)3414,3054,2961,2926,1591,1485,1447,1292,1230,1093,1019,853,737,700cm-1。
HRMS(LD+)计算值C38H30N2O(M+):530.2358,实测值:530.2350。
(S)-2-((2-异丙氧基苯基)(苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5c)由(2-异丙氧基苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇(86.7mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E制备(洗脱液:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为92%(88.9mg,92%ee)。
[α]D 26:-9.4(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:7.0分钟(次要),15.0分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.47(s,1H),9.28(s,1H),7.42(d,J=8.1Hz,1H),7.34–7.05(m,8H),7.02–6.87(m,7H),6.73(t,J=7.6Hz,2H),6.61(td,J1=2.7Hz,J2=1.6Hz,1H),5.95(q,J=2.8Hz,1H),5.81(td,J1=3.1Hz,J2=1.6Hz,1H),4.35(hept,J=6.0Hz,1H),0.83(d,J=6.0Hz,3H),0.63(d,J=5.9Hz,3H)。
13C NMR(100MHz,丙酮-d6)δ156.0,144.9,138.0,136.8,135.4,135.3,135.0,131.4,131.2,130.9,130.9,129.4,127.6,127.6,126.7,125.7,122.1,119.8,119.7,119.6,117.9,116.2,113.0,111.8,110.6,107.8,68.6,56.3,21.6,20.9。
IR(薄膜)3445,3417,3056,2976,2929,1592,1483,1449,1289,1242,1118,952,751,705cm-1。
HRMS(LD+)计算值C34H30N2O(M+):482.2358,实测值:482.2339。
(S)-2-((2-(甲氧基甲氧基)苯基)(苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5d)由(2-(甲氧基甲氧基)苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇(87.1mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E制备(洗脱液:己烷/乙酸乙酯=20:1→15:1),为白色泡沫,产率为78%(75.9mg,97%ee)。
[α]D 26:-1.9(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:4.5分钟(次要),12.0分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.47(s,1H),9.32(s,1H),7.41(d,J=8.1Hz,1H),7.26–7.19(m,3H),7.17–7.04(m,5H),7.01–6.78(m,9H),6.64–6.64(m,1H),5.99–5.96(m,1H),5.86–5.83(m,1H),4.51(d,J=6.9Hz,1H),4.45(d,J=6.9Hz,1H),2.81(s,3H)。
13C NMR(100MHz,丙酮-d6)δ156.7,145.0,137.5,136.7,135.6,135.5,135.3,131.3,131.0,130.9,130.7,129.6,127.8,127.6,126.8,125.8,122.2,121.6,119.9,119.6,118.3,116.4,115.6,111.9,110.4,107.9,94.78,56.3,55.6。
IR(薄膜)3443,3054,2954,2933,1592,1484,1234,1153,1078,996,917,737,705cm-1。
HRMS(LD+)计算值C33H28N2O2(M+):484.2151,实测值:484.2168。
(S)-2-((2,4-二甲氧基苯基)(苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5e)由(2,4-二甲氧基苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇(87.0mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E制备(洗脱剂:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为94%(91.3mg,96%ee)。
[α]D 26:-4.6(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:6.7分钟(次要),14.6分钟(主要)。
1H NMR(400MHz,CD2Cl2)δ8.45(s,1H),8.42(s,1H),7.38(d,J=7.9Hz,1H),7.32(d,J=8.1Hz,1H),7.23–7.14(m,6H),7.10–7.00(m,4H),6.92–6.89(m,3H),6.61–6.59(m,1H),,6.36–6.33(m,2H),6.13–6.10(m,1H),5.91–5.00(m,1H),3.78(s,3H),3.33(s,3H)。
13C NMR(100MHz,CD2Cl2)δ161.0,158.9,144.3,137.6,135.7,135.6,134.3,131.8,130.8,130.5,130.4,127.8,127.4,126.9,126.0,125.6,122.2,120.0,119.6,117.0,115.8,111.0,109.9,108.3,104.5,100.7,55.9,55.7,55.2。
IR(薄膜)3434,3410,3052,2926,2843,1606,1493,1451,1414,1301,1260,1030,735,701cm-1。
HRMS(LD+)计算值C33H28N2O2(M+):484.2151,实测值:484.2163。
(S)-3-苯基-2-(苯基)(1H-吡咯-2-基)(2-(三氟甲氧基)苯基)甲基)-1H-吲哚(5f)由)苯基(3-苯基-1H-吲哚-2-基)(2-(三氟甲氧基)苯基)甲醇(91.9mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E(7.5mol%催化剂)制备(洗脱液:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为85%(86.5mg,94%ee)。
[α]D 26:+14.1(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:4.0分钟(次要),11.8分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.58(s,1H),9.45(s,1H),7.43(d,J=8.2Hz,1H),7.27–7.04(m,10H),7.01–6.93(m,4H),6.89–6.86(m,3H),6.73–6.71(m,1H),6.03–6.01(m,1H),5.90–5.88(m,1H)。
13C NMR(100MHz,丙酮-d6)δ149.2,144.2,136.8,136.3,136.1,135.8,134.4,131.9,131.4,130.9,130.4,123.0,128.2,127.7,127.2,126.0,125.7,122.6,120.7(q,J=255.9Hz),120.0,119.8,119.1,117.8(q,J=2.2Hz),117.2,112.0,110.7,108.1,56.1。
19F NMR(376MHz,丙酮-d6)δ-56.3。
IR(薄膜)3445,3055,1487,1449,1251,1212,1160,898,739,704cm-1。
HRMS(LD+)计算值C32H23F3N2O(M+):508.1762,实测值:508.1745。
(S)-2-((2-氟-4-甲氧基苯基)(苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5g)由(2-氟-4-甲氧基苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇(84.7mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E制备(洗脱剂:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为95%(89.9mg,92%ee)。
[α]D 26:+12.4(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有7%i-PrOH的己烷;1.0mL/min;保留时间:24.4分钟(次要),25.4分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.49(s,1H),9.47–9.42(m,1H),7.41(d,J=8.2Hz,1H),7.23–7.15(m,6H),7.12–7.08(m,1H),7.03–6.94(m,4H),6.93–6.88(m,2H),6.83(t,J=9.0Hz,1H),6.70–6.68(m,1H),6.54(dd,J1=8.9,J2=2.6Hz,1H),6.26(dd,J1=13.0,J2=2.6Hz,1H),6.02–6.00(m,1H),5.92–5.90(m,1H),3.72(s,3H)。
13C NMR(100MHz,丙酮-d6)δ162.2(d,J=247.5Hz),161.5(d,J=10.0Hz),144.8,136.8,136.4,135.7,134.8,131.7(d,J=5.3Hz),131.4,130.9,130.4,128.3,127.7,127.4,125.9,125.6(d,J=12.3Hz),122.5,120.0,119.8,118.8,116.9,112.0,110.4(d,J=2.0Hz),109.5(d,J=2.7Hz),108.0,103.0(d,J=26.4Hz),55.8,54.8。
19F NMR(376MHz,丙酮-d6)δ-100.4。
IR(薄膜)4039,3054,3024,2962,1617,1578,1497,1450,1306,1260,1158,740,706cm-1。
HRMS(LD+)计算值C32H25FN2O(M+):472.1951,实测值:472.1943。
(S)-2-((2-甲氧基苯基)(苯基)(1H-吡咯-2-基)甲基)-5-甲基-3-苯基-1H-吲哚(5h)由(2-甲氧基苯基)(6-甲基-3-苯基-1H-吲哚-2-基)(苯基)甲醇(83.9mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E制备(洗脱剂:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为67%(62.6mg,94%ee)。
[α]D 26:+0.8(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:7.4分钟(次要),10.9分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.29(s,1H),9.27(s,1H),7.28(d,J=8.2Hz,1H),7.21–7.08(m,6H),7.00(s,1H),6.97–6.83(m,7H),6.76(td,J1=7.6Hz,J2=1.2Hz,1H),6.71(dd,J1=8.2Hz,J2=1.2Hz,1H),6.63–6.61(m,1H),5.95(dt,J1=3.4Hz,J2=2.5Hz,1H),5.79(dd,J1=3.3Hz,J2=1.6Hz,1H),3.19(s,3H),2.32(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.7,145.1,137.8,136.9,135.64,135.1,133.9,131.3,131.2,131.0,130.7,129.7,128.6,127.7,127.6,126.8,125.7,123.7,120.8,119.2,118.1,115.9,113.5,111.6,110.4,107.8,56.2,55.5,21.6。
IR(薄膜)3442,3421,3051,3023,2961,1591,1543,1250,1088,1021,797,733,702cm-1。
HRMS(LD+)计算值C33H28N2O(M+):468.2202,实测值:468.2214。
(S)-5-甲氧基-2-((2-甲氧基苯基)(苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5i)由(6-甲氧基-3-苯基-1H-吲哚-2-基)(2-甲氧基苯基)(苯基)甲醇(87.1mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E(使用4mL DCM,36小时)制备(洗脱液:己烷/乙酸乙酯=20∶1→15∶1),产率为78%(75.8mg,96%ee)。
[α]D 26:-1.5(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:8.1分钟(次要),13.8分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.28(s,1H),9.24(s,1H),7.30(d,J=8.5Hz,1H),7.21–7.08(m,6H),6.99–6.93(m,4H),6.89–6.83(m,2H),6.79–6.71(m 4H),6.63–6.61(m,1H),5.97–5.95(m,1H),5.85–5.73(m,1H),3.67(s,3H),3.20(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.7,155.1,145.0,138.5,136.9,135.6,135.1,131.2(2C),131.0,130.7,130.6,129.7,127.72,127.69,126.8,125.8,120.8,118.1,116.1,113.5,112.6,112.3,110.4,107.9,101.5,56.3,55.8,55.6。
IR(薄膜)3442,3054,2942,2832,1589,1482,1443,1255,1150,1027,799,738,706cm-1。
HRMS(LD+)计算值C33H28N2O2(M+):484.2151,实测值:484.2138。
(S)-5-氟-2-((2-甲氧基苯基)(苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5j)由(6-氟-3-苯基-1H-吲哚-2-基)(2-甲氧基苯基)(苯基)甲醇(84.7mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E(使用4mL DCM,36小时)制备(洗脱液:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为68%(63.8mg,95%ee)。
[α]D 26:-3.2(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:6.6分钟(小),8.3分钟(大)。
1H NMR(400MHz,CD2Cl2)δ8.48(s,1H),8.39(s,1H),7.28–7.14(m,7H),7.01–6.97(m,5H),6.91(td,J1=9.1Hz,J2=2.5Hz,1H),6.84–6.77(m,4H),6.60–6.58(m,1H),6.09–6.07(m,1H),5.86–5.82(m,1H),3.31(s,3H)。
13C NMR(100MHz,CD2Cl2)δ158.5(d,J=231.9Hz),158.1,143.6,139.4,135.1(d,J=14.6Hz),133.3,131.0,130.8,130.6,130.4,129.5,127.8,127.6,127.1,125.9,121.0,117.2,116.1(d,J=4.7Hz),113.4,111.8(d,J=9.6Hz),110.4,110.1,108.4,108.1,104.3(d,J=23.8Hz),103.9,56.0,55.8。
19F NMR(376MHz,CD2Cl2)δ-128.6。
IR(薄膜)3439,3411,2054,2935,2834,1588,1481,1440,1249,1102,1022,907,857,751,704cm-1。
HRMS(LD+)计算值C32H25FN2O(M+):472.1951,实测值:472.1963。
(S)-2-((2-甲氧基苯基)(1H-吡咯-2-基)(对甲苯基)甲基)-3-苯基-1H-吲哚(5k)由(2-甲氧基苯基)(3-苯基-1H-吲哚-2-基)(对甲苯基)甲醇(81.9mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E制备(洗脱液:己烷乙酸乙酯=20:1→15:1),为白色泡沫,产率为96%(90.2mg,92%ee)。
[α]D 26:-1.5(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:5.3分钟(次要),11.4分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.38(s,1H),9.29(s,1H),7.40(d,J=8.0Hz,1H),7.27(d,J=8.0Hz,1H),7.17–6.85(m,13H),6.79–6.75(m,1H),6.71(d,J=2.8Hz,1H),6.65–6.59(m,1H),5.99(d,J=8.0Hz,1H),5.84–5.87(m,1H),3.21(s,3H),2.26(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.7 141.9,137.9,136.7 136.0,135.7,135.4,134.9,131.2,130.9,130.7(2C),129.5,128.4,127.5,125.6,122.0,120.7,119.8,119.5,118.0,116.0,113.4,111.8,110.3,107.8,55.8,55.5,21.0。
IR(薄膜)3436,3423,3051,3019,2961,2929,2590,1484,1251,1180,1092,1021,804,740,704cm-1。
HRMS(LD+)计算值C33H28N2O(M+):468.2202,实测值:468.2213。
(S)-2-((2-甲氧基苯基)(4-甲氧基苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5l)由(2-甲氧基苯基)(4-甲氧基苯基)(3-苯基-1H-吲哚-2-基)甲醇(87.1mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E制备(洗脱液:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为78%(75.7mg,86%ee)。
[α]D 26:-1.5(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK OD-H柱;含有5%的i-PrOH的己烷;1.0mL/min;保留时间:7.9分钟(次要),9.3分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.37(s,1H),9.29(s,1H),7.40(d,J=8.1Hz,1H),7.29–7.03(m,5H),7.03–6.83(m,7H),6.80–6.57(m,5H),5.98–5.96(m,1H),5.83–5.81(m,1H),3.72(s,3H),3.23(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.8,158.7,138.2,136.8,136.7,136.0,135.4,135.1,131.9,131.3,130.91,130.88,129.6,127.6,125.7,122.1,120.8,119.8,119.5,118.0,115.9,113.4,113.0,111.8,110.3,107.8,55.6,55.5,55.4。
IR(薄膜)3435,3413,3049,2958,2835,1595,1452,1245,1177,1095,1024,800,729,703cm-1。
HRMS(LD+)计算值C33H28N2O2(M+):484.2151,实测值:484.2168。
(S)-2-((2-甲氧基苯基)(4-(甲硫基)苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5m)由(2-甲氧基苯基)(4-(甲硫基)苯基)(3-苯基-1H-吲哚-2-基)甲醇(90.2mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E(使用4mL DCM,36小时)制备(洗脱液:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为71%(70.9mg,83%ee)。
[α]D 26:-4.8(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:6.3分钟(次要),10.8分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.40(s,1H),9.32(s,1H),7.40(d,J=8.1Hz,1H),7.23–7.16(m,2H),7.10–7.06(m,3H),7.03–6.84(m,9H),6.79(t,J=7.6Hz,1H),6.74(d,J=8.1Hz,1H),6.67–6.62(m,1H),5.99–5.96(m,1H),5.84–5.82(m,1H),3.23(s,3H),2.42(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.7,141.6,137.8,136.82,136.77,135.6,135.5,134.9,131.4,131.3,131.0,130.9,129.7,127.6,125.8,125.7,122.2,120.9,119.9,119.6,118.2,116.2,113.5,111.9,110.4,107.9,55.9,55.6,15.6。
IR(薄膜)3437,3051,2927,2834,1590,1485,1450,1250,1023,812,739,708cm-1。
HRMS(LD+)计算值C33H28N2OS(M+):500.1922,实测值:500.1904。
(S)-2-((4-氟苯基)(2-甲氧基苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5n)由(4-氟苯基)(2-甲氧基苯基)(3-苯基-1H-吲哚-2-基)甲醇(84.7mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E(使用4mL DCM,36小时)制备(洗脱液:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为68%(63.8mg,95%ee)。
[α]D 26:+7.4(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:6.6分钟(次要),14.5分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.45(s,1H),9.38(s,1H),7.40(d,J=8.1Hz,1H),7.24–7.13(m,4H),7.11–7.06(m,1H),7.00–6.90(m,5H),6.88–6.73(m,6H),6.67–6.65(m,1H),6.00–5.97(m,1H),5.83–5.81(m,1H),3.23(s,3H)。
13C NMR(100MHz,丙酮-d6)δ161.9(d,J=241.7Hz),158.6,140.5(d,J=3.3Hz),137.6,136.7,135.6,135.5,135.1,132.5(d,J=7.9Hz),131.3,130.9,130.8,129.9,127.7,125.8,122.3,120.9,119.9,119.7,118.4,116.4,114.0(d,J=21.0Hz),113.5,111.9,110.3,107.9,55.8,55.5。
19F NMR(376MHz,丙酮-d6)δ-119.1。
IR(薄膜)3441,3415,3052,2934,2837,1595,1494,1236,1164,1098,1023,821,741,706cm-1。
HRMS(LD+)计算值C32H25FN2O(M+):472.1951,实测值:472.1971。
(S)-2-((2-甲氧基苯基)(1H-吡咯-2-基)(4-(三氟甲基)苯基)甲基)-3-苯基-1H-吲哚(5o)由(2-甲氧基苯基)(3-苯基-1H-吲哚-2-基)(4-(三氟甲基)苯基)甲醇(94.7mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E(在40℃下,36小时)制备(洗脱液:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为85%(84.1mg,83%ee)。
[α]D 26:+14.5(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:4.0分钟(次要),6.2分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.54(s,1H),9.50(s,1H),7.41(d,J=8.1Hz,1H),7.38–7.33(m,4H),7.27–7.19(m,2H),7.13–7.09(m,1H),7.01–6.95(m,5H),6.90–6.83(m,3H),6.78(d,J=8.2Hz,1H),6.72–6.69(m,1H),6.05–6.00(m,1H),5.86–5.84(m,1H),3.22(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.4,148.8,136.9,136.6,135.5,135.0,134.8,131.33,131.32,130.90,130.89,130.1,128.2(q,J=31.6Hz),127.7,126.0,125.5(q,J=269.6Hz),124.2(q,J=3.9Hz),122.4,121.1,120.0,119.7,118.7,116.8,113.5,111.9,110.4,108.1,56.3,55.4。
19F NMR(376MHz,丙酮-d6)δ-62.6。
IR(薄膜)3436,3416,3054,2961,2837,1590,1483,1324,1164,1116,1018,801,737,705cm-1。
HRMS(LD+)计算值C33H25F3N2O(M+):522.1919,实测值:522.1934。
(S)-2-((2-甲氧基苯基)(3-甲氧基苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5p)由(2-甲氧基苯基)(3-甲氧基苯基)(3-苯基-1H-吲哚-2-基)甲醇(87.1mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E制备(洗脱剂:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为90%(87.5mg,96%ee)。
[α]D 26:+6.5(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:5.5分钟(次要),9.1分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.43(s,1H),9.31(s,1H),7.41(d,J=8.1Hz,1H),7.28–7.25(m,1H),7.20–7.14(m,1H),7.11–6.90(m,9H),6.83–6.67(m,5H),6.64–6.62(m,1H),5.99–5.97(m,1H),5.88–5.86(m,1H),3.60(s,3H),3.22(s,3H)。
13C NMR(100MHz,丙酮-d6)δ159.7,158.8,146.5,137.7,136.7,135.4,135.3,134.9,131.2,130.94,130.87,129.7,128.6,127.6,125.7,123.3,122.2,120.9,119.9,119.6,118.0,117.3,116.2,113.4,111.85,111.78,110.4,107.9,56.2,55.6,55.2。
IR(薄膜)3437,3052,2939,2834,1593,1483,1244,1178,1028,799,739,704cm-1。
HRMS(LD+)计算值C33H28N2O2(M+):484.2151,实测值:484.2170。
(S)-2-((苯并[d][1,3]二氧杂环戊烷-5-基)(2-甲氧基苯基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5q)由(苯并[d][1,3]二氧杂环戊烷-5-基)(2-甲氧基苯基)(3-苯基-1H-吲哚-2-基)甲醇(89.9mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E制备(洗脱液:己烷/乙酸乙酯=20:1→15:1),为白色泡沫,产率为90%(90.0mg,94%ee)。
[α]D 26:+10.8(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:6.6分钟(次要),15.1分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.44(s,1H),9.35(s,1H),7.40(d,J=8.1,1H),7.24–7.15(m,2H),7.10–7.06(m,1H),7.02–6.86(m,7H),6.82–6.75(m,2H),6.68–6.62(m,2H),6.57–6.54(m,2H),5.99–5.96(m,1H),5.86–5.83(m,3H),3.27(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.8,147.5,146.6,138.5,138.1,136.9,135.7,135.4,135.1,131.2,130.92,130.90,129.7,127.6,125.7,124.1,122.2,120.9,119.9,119.6,118.1,116.2,113.6,111.9,111.8,110.3,107.9,107.3,101.7,56.1,55.7。
IR(薄膜)3437,3052,2890,2836,1592,1485,1428,1238,1034,934,809,737,708cm-1。
HRMS(LD+)计算值C33H26N2O3(M+):498.1943,实测值:498.1919。
(S)-2-((2-甲氧基苯基)(萘-2-基)(1H-吡咯-2-基)甲基)-3-苯基-1H-吲哚(5r)由(2-甲氧基苯基)(萘-2-基)(3-苯基-1H-吲哚-2-基)甲醇(91.1mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E(使用4mL DCM,36h)制备(洗脱液:己烷/乙酸乙酯=20:1→15:1),为白色泡沫,产率70%(70.6mg,95%ee)。
[α]D 26:-15.0(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:5.3分钟(次要),10.5分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.52(s,1H),9.40(s,1H),7.78(d,J=7.8Hz,1H),7.74(s,1H),7.64(d,J=8.0Hz,1H),7.60(d,J=8.7Hz,1H),7.45–7.34(m,3H),7.32–7.16(m,3H),7.11–7.08(m,1H),7.00–6.96(m,2H),6.94–6.73(m,7H),6.69–6.64(m,1H),6.02–5.98(m,1H),5.89–5.87(m,1H),3.18(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.9,142.7,137.8,136.8,135.6,135.5,134.8,133.7,133.0,131.3,131.1,131.0,129.82,129.80,129.2,129.0,128.0,127.6,126.8,126.4,126.3,125.8,122.1,120.9,119.9,119.6,118.3,116.2,113.5,112.0,110.5,108.0,56.3,55.6。
IR(薄膜)3434,3051,2963,2936,1592,1485,1425,1251,1177,1097,1023,809,739,706cm-1。
HRMS(LD+)计算值C36H28N2O(M+):504.2202,实测值:504.2191。
(R)-2-((2-甲氧基苯基)(1H-吡咯-2-基)(噻吩-3-基)甲基)-3-苯基-1H-吲哚(5s)由(2-甲氧基苯基)(3-苯基-1H-吲哚-2-基)(噻吩-3-基)甲醇(82.3mg,0.2mmol)和吡咯(26.8mg,0.4mmol)根据通用步骤E制备(洗脱剂:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率31%(28.3mg,95%ee)。
[α]D 26:-12.9(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有10%i-PrOH的己烷;1.0mL/min;保留时间:6.3分钟(次要),13.0分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.38(s,1H),9.37(s,1H),7.40(d,J=8.1Hz,1H),7.24(d,J=8.0Hz,1H),7.17–7.12(m,2H),7.09–7.05(m,1H),7.00–6.85(m,8H),6.80–6.69(m,3H),6.64–6.62(m,1H),5.96(q,J=2.8Hz,1H),5.81–5.79(m,1H),3.29(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.8,145.8,138.1,136.7,135.51,135.46,134.6,131.2,131.0,130.9,130.5,129.7,127.7,125.8,124.5,124.2,122.1,120.8,119.9,119.6,118.1,115.4,113.3,111.9,109.7,107.9,55.7,53.1。
IR(薄膜)3417,3051,2927,2841,1590,1544,1481,1425,1290,1242,1095,1025,847,801,737,704cm-1。
HRMS(LD+)计算值C30H24N2OS(M+):460.1609,实测值:460.1605。
(S)-2-((2-甲氧基苯基)(5-甲基-1H-吡咯-2-基)(苯基)甲基)-3-苯基-1H-吲哚(5t)由(2-甲氧基苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇(89.2mg,0.22mmol)和2-甲基吡咯(16.2mg,0.2mmol)根据通用步骤E(使用4mL DCM,24h)制备(洗脱液:己烷/乙酸乙酯=20:1→15:1),为白色泡沫,产率95%(89.3mg,88%ee)。
[α]D 26:-14.8(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK OD-H柱;含有3%i-PrOH的己烷;1.0mL/min;保留时间:5.5分钟(次要),6.3分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.45(s,1H),8.99(s,1H),7.39(d,J=8.1Hz,1H),7.31–7.07(m,8H),7.02–6.95(m,7H),6.84–6.74(m,2H),5.61–5.57(m,2H),3.20(s,3H),2.05(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.6,145.6,137.8,136.7,135.7,135.5,133.3,131.09,131.07,130.8,130.4,129.6,127.72,127.69,127.5,126.7,125.7,122.12,120.9,119.8,119.7,116.3,113.7,111.8,110.9,105.7,56.2,55.6,13.1。
IR(薄膜)3439,3411,3054,2932,2790,1588,1484,1248,1178,1106,1021,743,698cm-1。
HRMS(LD+)计算值C33H28N2O(M+):468.2202,实测值:468.2213。
(S)-2-((5-乙基-1H-吡咯-2-基)(2-甲氧基苯基)(苯基)甲基)-3-苯基-1H-吲哚(5u)由(2-甲氧基苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇(89.2mg,0.22mmol)和2-乙基吡咯(19.0mg,0.2mmol)根据通用步骤E(使用4mL DCM,36小时)制备(洗脱液:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为93%(89.7mg,84%ee)。
[α]D 26:-11.9(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有3%i-PrOH的己烷;1.0mL/min;保留时间:4.8分钟(次要),5.7分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.44(s,1H),9.00(s,1H),7.39(d,J=8.1Hz,1H),7.29(d,J=7.9Hz,1H),7.22–7.06(m,7H),7.03–6.91(m,7H),6.84–6.74(m,2H),5.61(s,2H),3.21(s,3H),2.43(q,J=7.6Hz,2H),1.10(t,J=7.5Hz,3H)。
13C NMR(100MHz,丙酮-d6)δ158.6,145.6,137.9,136.7,135.8,135.5,134.4,133.2,131.1(2C),130.8,130.4,129.6,127.7,127.5,126.8,125.7,122.1,120.9,119.8,119.7,116.3,113.7,111.8,110.8,103.8,56.3,55.6,21.2,14.2。
IR(薄膜)3442,3416,3053,2966,2932,2883,1589,1451,1250,1177,1107,1023,740,700cm-1。
HRMS(LD+)计算值C34H30N2O(M+):482.2358,实测值:482.2339。
(S)-2-((2-甲氧基苯基)(4+-甲基-1H-吡咯-2-基)(苯基)甲基)-3-苯基-1H-吲哚(5v)和(R)-2-((2-甲氧基苯基)(3-甲基-1H-吡咯-2-基)(苯基)甲基)-3-苯基-1H-吲哚(5v')由(2-甲氧基苯基)(苯基)(3-苯基-1H-吲哚-2-基)甲醇(89.2mg,0.22mmol)和3-甲基吡咯(32.4mg,0.4mmol)根据通用步骤E(使用4mL DCM,36小时)制备(洗脱液:己烷/乙酸乙酯=20∶1→15∶1),为白色泡沫,产率为90%(84.4mg,5v/5v'=6.7/1)。
通过非手性HPLC柱进行纯化获得用于表征的主要产物5v的纯样品,主要产物5v的分析数据如下。
[α]D 26:-4.4(c=1.0,氯仿)。产物的HPLC分析:Daicel CHIRALPAK AD-H柱;含有5%的i-PrOH的己烷;1.0mL/min;保留时间:6.1分钟(次要),11.0分钟(主要)。
1H NMR(400MHz,丙酮-d6)δ9.43(s,1H),8.95(s,1H),7.39(d,J=8.1Hz,1H),7.25–7.04(m,9H),6.97–6.93(m,5H),6.88–6.82(m,2H),6.78(d,J=7.6Hz,1H),6.69(d,J=8.1Hz,1H),6.37(s,1H),5.61(s,1H),3.18(s,3H),1.95(s,3H)。
13C NMR(100MHz,丙酮-d6)δ158.7,145.2,137.8,136.8,135.5,135.6,135.2,131.3,131.00,130.96,130.7,129.7,127.7,127.5,126.8,125.7,122.1,120.8,119.8,119.6,117.7,116.3,116.2,113.5,112.3,111.9,56.3,55.5,12.3。
IR(薄膜)3416,3053,2927,2867,2542,1589,1483,1449,1242,1178,1110,1023,980,803,738,698cm-1。
HRMS(LD+)计算值C33H28N2O(M+):4.2202,实测值:468.2205。
合成三芳基甲醇底物
通用步骤A
在0℃下,向4-溴苯酚(0.78g,4.5mmol)在THF(30mL)中的搅拌溶液中缓慢加入叔丁基锂(1.6M,在戊烷中,9.3mL,14.9mmol)。将所得混合物在0℃下搅拌2小时。接下来,加入S1(3mmol)(Ip,H.-W.;Ng,C.-F.;Chow,H.-F.;Kuck,D.J.Am.Chem.Soc.2016,138,1377813781.Ma,S.;Liu,J.X.;Li,S.H.;Chen,B.;Cheng,J.J.;Kuang,J.Q.;Liu,Y.;Wan,B.Q.;Wang,Y.L.;Ye,J.T.;Yu,Q.;Yuan,W.M.;Yu,S.C.Adv.Synth.Catal.2011,353,1005-1017)在THF(10mL)中的溶液中的溶液,并将反应混合物保持搅拌过夜。加入饱和NH4Cl水溶液以淬灭反应。反应混合物用乙酸乙酯)萃取(3×30mL)。合并的有机层经无水Na2SO4干燥,过滤并浓缩。残余物通过硅胶快速色谱纯化,得到纯的叔醇1。
通用步骤B
在0℃下,向4-溴苯酚(1.30g,7.5mmol)在THF(50mL)中的搅拌溶液中缓慢加入叔丁基锂(1.6M,在戊烷中,15.5mL,24.8mmol)。将所得混合物在0℃下搅拌2小时。之后,加入S2(3mmol)(Soldi,C.;Lamb,K.N.;Squitieri,R.A.;Gonzalez-López,M.;Maso,D.;M.J.;Shaw,J.T.J.Am.Chem.Soc.2014,136,15142-15145.)在THF(10mL)中的溶液,并将反应混合物保持搅拌过夜。加入饱和NH4Cl水溶液以淬灭反应。反应混合物用乙酸乙酯)萃取(3×30mL)。合并的有机层经无水Na2SO4干燥,过滤并浓缩。残余物通过硅胶快速色谱纯化,得到纯的叔醇1。
通用步骤C
在0℃下,向S3(2mmol)(Katritzky,A.R;Lue,P.;Chen,Y.X.J.Org.Chem.1990,55,3688-3691)在THF(20mL)中的搅拌溶液中缓慢加入叔丁基锂(1.6M,在戊烷中,1.3mL,2.1mmol)。将所得混合物在0℃下搅拌0.5小时。之后,加入S2(2mmol)在THF(10mL)中的溶液,并将反应混合物在室温下搅拌过夜。加入饱和NH4Cl水溶液以淬灭反应。将反应混合物用乙酸乙酯萃取3次(3×30mL)。合并的有机层经无水Na2SO4干燥,过滤并浓缩。残余物通过硅胶快速色谱纯化,得到纯的叔醇4′。
向4'在THF(3mL)和乙醇(3mL)中的溶液中加入NaBH4(2.2mmol)。将反应混合物加热至回流,保持3小时,然后将其冷却至室温。加入饱和NH4Cl水溶液以淬灭反应。将反应混合物用乙酸乙酯萃取3次(3×20mL)。合并的有机层经无水Na2SO4干燥,过滤并浓缩。残余物通过硅胶快速色谱纯化,得到纯的叔醇4。
Claims (21)
1.一种用于制备具有式I的四芳基甲烷的对映选择性方法:
其中Ar1、Ar2、Ar3、Ar4各自独立地是芳基或杂芳基;
所述方法包括:
在手性布朗斯特酸的存在下,在促进亲电芳香取代反应的条件下,使式II的化合物:
与杂芳族亲核试剂接触,从而形成式I的化合物,其中式I的化合物为手性的;
其中所述手性布朗斯特酸由式IIIg表示:
其中R5和R5’中的每一个是芳基或三芳基硅烷;
其中在手性布朗斯特酸的存在下使式II的化合物与杂芳族亲核试剂接触的步骤发生在选自由氯苯,PhCF3,PhF,CCl4,CH2Cl2(DCM),CHCl3,PhMe和ClCH2CH2Cl(DCE)组成的组的溶剂中;
其中在手性布朗斯特酸存在下使式II的化合物与杂芳族亲核试剂接触的步骤发生在-30℃和40℃之间的温度。
2.根据权利要求1所述的方法,其中,所述四芳基甲烷具有式Ia:
其中,
m和n各自独立地选自1、2、3或4;
Ar1是芳基或杂芳基;
Ar2是杂芳基;
R1和R2各自独立地选自由氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,氰基,硝基,叠氮基,-OR3,-OSi(R3)3,-O(C=O)R3,-(C=O)OR3,-O(C=O)OR3,-(C=O)R3,-N(R4)2,-N(R4)(C=O)R3,-(C=O)N(R4)2,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-(S=O)R3,-SO2R3,-SO2N(R4)2,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)3和-(P=O)(OR3)3组成的组;或两个R1与它们所连接的碳一起形成5-6元环烷基,杂环烷基,芳基或杂芳基;或两个R2与它们所连接的碳一起形成5-6元环烷基,杂环烷基,芳基或杂芳基;
R3选自由氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基和杂芳基组成的组;并且
对于每个实例,R4独立地选自由氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基和杂芳基组成的组;或两个R4与它们所连接的氮一起形成3-6元杂环烷基;或一个R3和一个R4与它们所连接的原子一起形成4-6元杂环烷基;并且所述方法包括:
在手性布朗斯特酸的存在下,在促进亲电芳香取代反应的条件下,使式IIa的化合物:
与杂芳族亲核试剂接触,从而形成式Ia的化合物。
3.根据权利要求2所述的方法,其中所述卤代烷基为全卤代烷基。
4.根据权利要求1所述的方法,其中所述手性布朗斯特酸是手性磷酸,所述手性磷酸由式IIIe表示:
其中R8是烷基、环烷基或芳基。
5.根据权利要求4所述的方法,其中R8是异丙基、环己基或苯基。
6.根据权利要求2所述的方法,其中式IIa的化合物由选自以下的结构表示:
其中
m是0、1、2或3;
p是0、1、2或3;
q是0、1或2;
Ar1选自由以下组成的组:
X是NR11、O、S或Se;
R1’选自由-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,
-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;R1’和一个R1与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基;
每个R9独立地选自由氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,氰基,硝基,叠氮基,-OR3,-OSi(R3)3,-O(C=O)R3,-(C=O)OR3,-O(C=O)OR3,-(C=O)R3,-N(R4)2,-N(R4)(C=O)R3,-(C=O)N(R4)2,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-(S=O)R3,-SO2R3,-SO2N(R4)2,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)3和-(P=O)(OR3)3组成的组;
R9’选自由-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,
-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;或两个R9’与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基;并且
R10选自由烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3或-SeR3组成的组;且
R11是氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,-(C=O)OR3,-(C=O)R3,-(C=O)N(R4)2,-SO2R3或-SO2N(R4)2。
7.根据权利要求6所述的方法,其中所述卤代烷基为全卤代烷基。
8.根据权利要求6所述的方法,其中,Ar1选自由以下组成的组:
9.根据权利要求2所述的方法,其中所述杂芳族亲核试剂由式IV表示:
其中
t是0、1、2或3;
Y是NR13、O、S或Se;
每个R12独立地选自由氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,氰基,硝基,叠氮基,-OR3,-OSi(R3)3,-O(C=O)R3,-(C=O)OR3,-O(C=O)OR3,-(C=O)R3,-N(R4)2,-N(R4)(C=O)R3,-(C=O)N(R4)2,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-(S=O)R3,-SO2R3,-SO2N(R4)2,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)3和-(P=O)(OR3)3组成的组;或两个R12与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基;并且
R13是氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,-(C=O)OR3,-(C=O)R3,-(C=O)N(R4)2,-SO2R3或-SO2N(R4)2。
10.根据权利要求9所述的方法,其中所述卤代烷基为全卤代烷基。
11.根据权利要求9所述的方法,其中,Y为NR13;
每个R12独立地选自由氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,氰基,硝基,叠氮基,-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-SO2N(R4)2,-N(R4)SO2R3和-SeR3组成的组;或两个R12与它们所连接的碳一起形成6元环烷基或芳基;并且
R13是氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基或杂芳基。
12.根据权利要求11所述的方法,其中所述卤代烷基为全卤代烷基。
13.根据权利要求2所述的方法,其中式IIa的化合物由选自以下的结构表示:
其中,
m是0、1、2或3;
p是0、1、2或3;
q是0、1或2;
Ar1选自由以下组成的组:
X是S或NR11;
R1’选自由-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,
-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;或R1’和一个R1与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基;
每个R9独立地选自由氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,氰基,硝基,叠氮基,-OR3,-OSi(R3)3,-O(C=O)R3,-(C=O)OR3,-O(C=O)OR3,-(C=O)R3,-N(R4)2,-N(R4)(C=O)R3,-(C=O)N(R4)2,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-(S=O)R3,-SO2R3,-SO2N(R4)2,-N(R4)SO2R3,-SeR3,-P(R3)3,-P(OR3)3和-(P=O)(OR3)3组成的组;
R9’选自由-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,
-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;或两个R9’与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基;且
R10选自由烷基,卤代烷基,环烷基,杂环烷基,芳基,芳烷基和杂芳基组成的组;和
R11是氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基或杂芳基;和
所述杂芳族亲核试剂由式IV表示:
其中
t是0、1、2或3;
Y是NR13;
每个R12独立地选自由氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,叠氮基,-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;或两个R12与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基;并且
R13是氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基或杂芳基。
14.根据权利要求13所述的方法,其中所述卤代烷基为全卤代烷基。
15.根据权利要求13所述的方法,其中,m是0或1;R1’是-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3或-O(C=O)N(R4)2;
Ar1选自由以下组成的组:
其中
P是0或1;
q是0或1;
R9’选自由-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3或-O(C=O)N(R4)2组成的组;且
R10是芳基;且
所述杂芳族亲核试剂选自:
其中
t是0或1;且
每个R12独立地选自由氢,烷基,卤代烷基,烯基,炔基,环烷基,杂环烷基,芳基,芳烷基,杂芳基,叠氮基,-OR3,-OSi(R3)3,-O(C=O)R3,-O(C=O)OR3,-N(R4)2,-N(R4)(C=O)R3,-N(R4)(C=O)N(R4)2,-N(R4)(C=O)OR3,-O(C=O)N(R4)2,-SR3,-N(R4)SO2R3,-SeR3,-P(R3)3和-P(OR3)3组成的组;或两个R12与它们所连接的碳一起形成5-6元环烷基、杂环烷基、芳基或杂芳基。
16.根据权利要求15所述的方法,其中所述卤代烷基为全卤代烷基。
17.根据权利要求1所述的方法,其中R5是2,4,6-(iPr)3C6H2-、2,4,6-Cy3C6H2-、1-萘基、9-蒽基,9-菲基、1-芘或2,6-iPr2-6-(9-蒽基)。
18.根据权利要求1所述的方法,其中相对于式II的化合物,手性布朗斯特酸以0.1%和25%之间的摩尔浓度存在。
19.根据权利要求1所述的方法,其中以40%至99.9%的对映体过量(ee)制备具有式I的四芳基甲烷。
20.根据权利要求11所述的方法,其中以80%至97%的ee制备具有式I的四芳基甲烷。
21.根据权利要求1所述的方法,其中式II的化合物是外消旋混合物。
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Enantioselective Synthesis of Triarylmethanes by Chiral Imidodiphosphoric Acids Catalyzed Friedel−Crafts Reactions;Ming-Hua Zhuo等;《Org. Lett.》;第16卷;1096-1099 * |
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