CN107501160A - 一种有机催化合成轴手性芳基吲哚的方法 - Google Patents
一种有机催化合成轴手性芳基吲哚的方法 Download PDFInfo
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- CN107501160A CN107501160A CN201710798870.1A CN201710798870A CN107501160A CN 107501160 A CN107501160 A CN 107501160A CN 201710798870 A CN201710798870 A CN 201710798870A CN 107501160 A CN107501160 A CN 107501160A
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- nmr
- cdcl
- tert
- compound
- aryl
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Links
- 238000000034 method Methods 0.000 title claims abstract description 56
- -1 aryl indole Chemical compound 0.000 title claims abstract description 32
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 14
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 14
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 125000003118 aryl group Chemical group 0.000 claims abstract description 36
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 13
- 125000001424 substituent group Chemical group 0.000 claims abstract description 10
- 229940125904 compound 1 Drugs 0.000 claims abstract description 9
- 229940125782 compound 2 Drugs 0.000 claims abstract description 9
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- DMLAVOWQYNRWNQ-UHFFFAOYSA-N azobenzene Chemical class C1=CC=CC=C1N=NC1=CC=CC=C1 DMLAVOWQYNRWNQ-UHFFFAOYSA-N 0.000 abstract description 18
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 7
- 238000007306 functionalization reaction Methods 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 138
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 54
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 46
- 238000005160 1H NMR spectroscopy Methods 0.000 description 43
- 238000004128 high performance liquid chromatography Methods 0.000 description 43
- 238000004896 high resolution mass spectrometry Methods 0.000 description 42
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 40
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 9
- 238000006254 arylation reaction Methods 0.000 description 8
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000006362 organocatalysis Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- WVPGIDWFLXGCLA-UHFFFAOYSA-N 2-tert-butyl-1h-indole Chemical class C1=CC=C2NC(C(C)(C)C)=CC2=C1 WVPGIDWFLXGCLA-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000004296 chiral HPLC Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JBIJLHTVPXGSAM-UHFFFAOYSA-N 2-naphthylamine Chemical class C1=CC=CC2=CC(N)=CC=C21 JBIJLHTVPXGSAM-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000010499 C–H functionalization reaction Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- KXMCMEVGEQMRIS-UHFFFAOYSA-N 1-tert-butylindole Chemical compound C1=CC=C2N(C(C)(C)C)C=CC2=C1 KXMCMEVGEQMRIS-UHFFFAOYSA-N 0.000 description 1
- LDJUYMIFFNTKOI-UHFFFAOYSA-N 2,2-dimethylbutanoyl chloride Chemical compound CCC(C)(C)C(Cl)=O LDJUYMIFFNTKOI-UHFFFAOYSA-N 0.000 description 1
- RFCQDOVPMUSZMN-UHFFFAOYSA-N 2-Naphthalenethiol Chemical compound C1=CC=CC2=CC(S)=CC=C21 RFCQDOVPMUSZMN-UHFFFAOYSA-N 0.000 description 1
- KLLLJCACIRKBDT-UHFFFAOYSA-N 2-phenyl-1H-indole Chemical compound N1C2=CC=CC=C2C=C1C1=CC=CC=C1 KLLLJCACIRKBDT-UHFFFAOYSA-N 0.000 description 1
- IGRCWJPBLWGNPX-UHFFFAOYSA-N 3-(2-chlorophenyl)-n-(4-chlorophenyl)-n,5-dimethyl-1,2-oxazole-4-carboxamide Chemical compound C=1C=C(Cl)C=CC=1N(C)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl IGRCWJPBLWGNPX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 238000006596 Alder-ene reaction Methods 0.000 description 1
- 229910014265 BrCl Inorganic materials 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- 229920002160 Celluloid Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- ASBLZFKHMYLYLH-UHFFFAOYSA-N NNc(ccc1c2)cc1ccc2-c1ccccc1 Chemical compound NNc(ccc1c2)cc1ccc2-c1ccccc1 ASBLZFKHMYLYLH-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000007281 aminoalkylation reaction Methods 0.000 description 1
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 1
- 238000005910 aminocarbonylation reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 238000006172 aromatic nitration reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000005347 biaryls Chemical group 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
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000013256 coordination polymer Substances 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
- 238000007333 cyanation reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N deuterated acetone Substances [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- CDXVUROVRIFQMV-UHFFFAOYSA-N oxo(diphenoxy)phosphanium Chemical compound C=1C=CC=CC=1O[P+](=O)OC1=CC=CC=C1 CDXVUROVRIFQMV-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 description 1
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 description 1
- PJGSXYOJTGTZAV-UHFFFAOYSA-N pinacolone Chemical compound CC(=O)C(C)(C)C PJGSXYOJTGTZAV-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
本发明公开了一种有机催化合成轴手性芳基吲哚的方法:以手性磷酸为催化剂,化合物1和化合物2反应:其中,R1为氢;R2选自叔丁基、1‑甲基环丙基、1‑甲基环丁基、叔戊基、芳基、杂芳基;R3表示任意的取代基,n表示1~4的整数,n为2以上时,所存在的2个以上的R3相同或不同;R4选自CO2R,R为烷基或苄基;R5表示任意的取代基,m表示1~4的整数,m为2以上时,所存在的2个以上的R5相同或不同。本发明的合成方法适用于多种酯的偶氮苯衍生物,以良好的收率、优异的对映体选择性获得了轴手性芳基吲哚,而且反应条件温和。本发明方法为有机催化不对称芳基官能化开辟了新的途径。
Description
技术领域
本发明属于有机合成领域,具体是一种有机催化合成轴手性芳基吲哚的方法。
背景技术
芳基化是有机化学的基本反应,主要通过芳基亲电取代或过渡金属催化的芳基官能化来实现。在芳基亲电取代中,芳环作为亲核试剂,芳香硝化、卤化、磺化、酰化和烷基化等许多重要转化可以通过芳基亲电取代进行。相对而言,涉及芳基C-H裂解的芳基亲核取代研究得很少。过去十年,芳环作为亲电体在许多有用的转化中(比如过渡金属催化的芳基C-H活化)与不同的亲核试剂反应,但涉及芳基亲核取代的有机催化芳基化仍有待探索。
在这方面,Nicewicz及其同事开创了使用吖啶光有机催化来产生芳基C-H胺化和氰化的自由基阳离子中间体。
尽管偶氮基团是一系列过渡金属催化的芳基碳氢键活化反应的导向基团,包括卤化、氧合、芳基化、酰化、氨化、氨基烷基化、氨基羰基化和环化,然而,偶氮苯衍生物的有机催化芳基化还未有报道。因此,使用偶氮基作为活化剂和导向基团,与有机催化剂反应是一种新颖而重要的反应,可为开发不对称有机催化提供新的途径。
轴手性联芳基化合物普遍存在于天然产物和生物活性化合物中,并作为手性配体或有机催化剂起着重要作用。由于该结构的重要性,催化对映选择性构建联芳基骨架引发了研究者的兴趣并取得了很大进展。与此形成鲜明对比的是,对映选择性合成轴手性芳基吲哚仍然面临着巨大挑战。因此,需要研究出新颖的对映选择性合成轴手性芳基吲哚的方法。
发明内容
发明人认为通过在芳环上引入吸电子官能团能使得芳环贫电子,易于芳香亲核取代反应发生,而吸电子官能团可以通过有机催化剂与芳烃官能团以氢键或离子键作用的形式获得。偶氮二甲酸酯是一种常见的有机试剂,广泛应用于有机合成中,如Mitsunobu反应、Diels-Alder反应、Ene反应等。其参与的有机催化的不对称反应也被广泛报道,通过手性氢键或手性布朗斯特酸与偶氮作用,实现不对称诱导。发明人设想,偶氮苯衍生物在适当有机催化剂存在下,通过激活偶氮官能团,使得N=N双键更加贫电子,由于N=N与芳环的共轭作用,这种贫电子属性可直接影响芳环的电性,使得芳香亲核取代易于发生。经过研究发现,使用磷酸作为催化剂,萘-2-硫醇可以和偶氮苯衍生物1a发生反应,形成联芳基硫醚,这表明有机催化芳基亲核取代是合理和可行的。
在新发现的偶氮苯衍生物的有机催化芳基化的基础上,发明人设想手性磷酸能有效活化吲哚,在提高偶氮苯衍生物亲电性的同时,也能提高吲哚亲核性,进而使得芳香亲核过程顺利发生。具体而言,如下式所示,偶氮苯衍生物1’与2-取代的吲哚2’发生芳基亲核取代,得到中间体A。
如果R1是H且R2是大的基团,进一步重新芳构化,通过中心手性至轴向手性转化形成轴手性芳基吲哚3’。在这种情况下,需要解决几个挑战:(a)寻找稳定的催化剂促使反应发生,更重要的是控制对偶氮苯衍生物的C/N化学选择性;(b)在亲核加成过程中寻找手性催化剂以控制对映体形成;(c)使用温和的反应条件来避免轴向旋转即外消旋化。
本发明的目的是通过手性磷酸催化的偶氮苯衍生物与2-取代吲哚的对映选择性芳基化,获得具有多种取代基的轴手性芳基吲哚。
为达到上述目的,本发明采用以下技术方案:
一种有机催化合成轴手性芳基吲哚3的方法,具体是:以手性磷酸为催化剂,化合物1和化合物2反应:
其中,
R1为氢;
R2选自叔丁基、1-甲基环丙基、1-甲基环丁基、叔戊基、芳基、杂芳基等位阻较大的基团;
R3表示任意的取代基,n表示1~4的整数,n为2以上时,所存在的2个以上的R3相同或不同;
R4选自CO2R,R为烷基或苄基;
R5表示任意的取代基,m表示1~4的整数,m为2以上时,所存在的2个以上的R5相同或不同。
在优选的方案中,
R1为氢;
R2选自叔丁基、1-甲基环丙基、叔戊基、苯基;
R3选自氢、烷基、卤素、烷氧基、苯基;
R4选自CO2R,R为烷基或苄基;
R5选自氢、烷基、卤素、烷氧基、苯基。
在更优选的方案中,
R1为氢;
R2选自叔丁基、1-甲基环丙基、叔戊基、苯基;
R3选自氢、甲基、卤素;
R4选自CO2R,R为甲基、乙基、叔丁基或苄基;
R5选自氢、甲基、卤素、甲氧基、苯基。
在优选的方案中,手性磷酸选自具有以下结构式的化合物:
以上列举的仅为较为常见的手性磷酸,经试验证实均能催化本发明的反应,可见该反应对于催化剂的种类要求并不严格,因此,其他结构的手性磷酸也可以催化化合物1和化合物2反应。
在更优选的方案中,所述手性磷酸为具有(R)-CP4或(R)-CP14结构式的化合物,(R)-CP4对于R2为烷基的底物具有较好的收率和对映选择性,(R)-CP14对于R2为芳基或杂芳基的底物具有较好的收率和对映选择性。
在优选的方案中,所述反应以二氯甲烷、甲苯、氯仿、二氯乙烷、乙腈、四氢呋喃、乙醚或乙酸乙酯为溶剂。
以上列举的仅为较为常见的溶剂,本发明的反应在这些溶剂中均能顺利进行,可见该反应对于溶剂的种类要求并不严格,因此,本发明的反应在其他溶剂中也能顺利进行。
在优选的方案中,所述催化剂的用量至少是1mol%。
反应的温度会影响反应完成的时间,温度越低,反应完成所需的时间越长,比如温度在0℃以下,反应也是可以进行的。从提高效率的角度考虑,在优选的方案中,所述反应的温度≥0℃。
化合物1和化合物2的摩尔比可以是任意的,在优选的方案中,化合物1和化合物2的摩尔比为1~1.5:1~1.5。
在最优选的方案中,以2.5mol%(R)-CP4为催化剂,甲苯为溶剂,化合物1和化合物2的摩尔比为1:1.1,室温反应。
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子的烷基,更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基的定义如上所述。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“卤素”指氟、氯、溴或碘。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,例如苯基和萘基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为5至10元,含1至3个杂原子;更优选为5元或6元,含1至2个杂原子;优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等,优选为咪唑基、吡唑基或嘧啶基、噻唑基;更有选吡唑基。
本发明具有以下有益效果:
本发明中,偶氮基团可以作为有机催化不对称芳基化的导向基团和活化基团,偶氮基团不仅可以有效地活化芳环以进行亲核攻击,而且可以有效地引导芳基亲核取代,通过偶氮苯衍生物的芳基亲核取代得到轴手性芳基吲哚。本发明的合成方法适用于多种酯的偶氮苯衍生物,包括甲酯、乙酯、叔丁酯、苄酯;芳香环上取代基的电子性质和位置对结果的影响有限,相应产物的产率为87~98%,ee值为94~99%;尽管大部分底物含有叔丁基,但是叔丁基可以换成其他大位阻基团如1-甲基环丙基,叔戊基或苯基,对相应产物的结果没有显着影响。本发明方法为有机催化不对称芳基官能化开辟了新的途径。
本发明的反应具有以下重要特征:(a)实现了偶氮苯衍生物作为亲电子体的有机催化芳基亲核取代;(b)偶氮基团作为有机催化不对称芳基化的诱导基团和活化基团;(c)以手性磷酸作为有机催化剂,以良好的收率、优异的对映体选择性获得了轴手性芳基吲哚;(d)催化剂负载量可以低至1mol%,反应条件温和。
具体实施方式
下面结合具体实施例对本发明做进一步的说明。
除非另有说明,化学品均购自商业化产品并且不用经进一步纯化。薄层色谱分析(TLC)使用60F254硅胶板。硅胶柱层析使用青岛海洋硅胶(粒径0.040-0.063mm)。TLC显色采用UV光(254nm)。1H NMR和13C NMR使用Bruker 400MHz或者500MHz核磁共振仪表征,溶剂为氘代氯仿、氘代丙酮或氘代DMSO,以四甲基硅烷(TMS)为内标。化学位移的单位是ppm,耦合常数的单位是Hz。在1H NMR中,δ表示化学位移,s表示单峰,d表示双峰,t表示三重峰,q表示四重峰,p表示五重峰,m表示多重峰,br表示宽峰。在13C NMR中,δ表示化学位移。通过Agilent手性HPLC仪器和大赛璐CHIRALCEL、CHIRALPAK色谱柱测定对映体过量值。高分辨质谱(HRMS)使用Q-Exactive(Thermo Scientific)Inc质谱设备。
第一部分:底物的合成
实施例1
底物1的合成
根据参考文献1、2制备芳环取代的β-萘胺1i-aaa(R5=6-Me),1k-aaa(R5=6-Ph),1l-aaa(R5=7-MeO),其他的β-萘胺可以商业化购买。
第一步:
根据参考文献3,在冰水浴中,将NaNO2(513mg,5.76mmol)的H2O(1mL)溶液慢慢地加入到相应胺(4.5mmol)在盐酸(5mL)中的悬浮液,所得溶液在冰水浴中搅拌1小时,并缓慢加入SnCl2·2H2O(3.556g,15.76mol),所得悬浮液在冰水浴中搅拌3.5小时,然后过滤。依次在0℃下用H2O(4×8mL)、室温下用H2O(1×8mL)、Et2O/正己烷(1:1,2×4mL)洗涤固体,固体干燥后得到所需产物。
按照通用方法,得到1i-aa,收率96%。
1H NMR(400MHz,DMSO-d6)δ10.46(s,3H),8.48(s,1H),7.73(d,J=8.9Hz,1H),7.65–7.56(m,2H),7.34–7.27(m,2H),7.21(dd,J=8.8,2.3Hz,1H),2.43(s,3H)。13C NMR(100MHz,DMSO-d6)δ142.6,132.7,131.6,128.9,128.7,128.0,126.5,126.2,117.0,108.0,21.0。HRMS(ESI)calcd for[M-Cl]C11H13N2,m/z:173.1073,found:173.1069。
按照通用方法,得到1k-aa,收率95%。
1H NMR(400MHz,DMSO-d6)δ10.40(s,3H),8.68(s,1H),8.14(s,1H),7.93(d,J=8.9Hz,1H),7.85–7.75(m,4H),7.54–7.46(m,2H),7.41–7.35(m,1H),7.33(d,J=2.1Hz,1H),7.27(dd,J=8.8,2.3Hz,1H)。13C NMR(100MHz,DMSO-d6)δ144.0,140.4,135.9,133.3,129.8,129.6,129.5,127.76,127.6,127.2,126.3,125.7,117.8,107.9。HRMS(ESI)calcdfor[M-Cl]C16H15N2,m/z:235.1230,found:235.1221。
第二步:
将相应的肼盐酸盐(10mmol)溶于CH3CN(20mL)中,加入吡啶(1.71mL,21.2mmol)。将溶液冷却至0℃,并在搅拌下滴加氯甲酸酯(1.04mL,11mmol),将反应混合物在0℃下搅拌15分钟,然后在室温下搅拌1小时。加入水(20mL),所得混合物用盐酸(6M)酸化至pH 4~6,产物用CH2Cl2(5×10mL)萃取,合并有机相,依次用饱和NaHCO3溶液(50mL)、饱和食盐水(50mL)洗涤,用Na2SO4干燥,将溶剂蒸发至干。粗产物通过硅胶柱色谱纯化,用PE/DCM洗脱,得到相应的产物。
按照通用方法,得到1d-a,收率81%。
1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),7.93(s,1H),7.75–7.66(m,2H),7.61(d,J=8.2Hz,1H),7.48–7.28(m,5H),7.27–7.09(m,2H),7.04(dd,J=8.8,2.3Hz,1H),6.91(s,1H),5.13(s,2H)。13C NMR(100MHz,DMSO-d6)δ157.3,147.6,137.4,134.8,129.0,128.9,128.4,128.3(2C),128.2,128.0(2C),126.7,126.3,122.7,116.3,104.8,66.2。HRMS(ESI)calcd for[M+H]C18H17N2O2,m/z:293.1285,found:293.1278。
按照通用方法,得到1h-a,收率46%。
1H NMR(400MHz,CDCl3)δ7.63(d,J=8.8Hz,1H),7.59(d,J=8.9Hz,1H),7.14–7.00(m,4H),6.62(s,1H),5.84(s,1H),3.89(s,3H),3.79(s,3H)。13C NMR(100MHz,CDCl3)δ157.6,156.1,143.9,130.3,129.7,128.1,128.1,119.2,116.1,107.8,106.1,55.3,53.0。HRMS(ESI)calcd for[M+H]C13H15N2O3,m/z:247.1077,found:247.1071。
按照通用方法,得到1i-a,收率86%。
1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.81(s,1H),7.61(d,J=8.8Hz,1H),7.55(d,J=8.4Hz,1H),7.48(s,1H),7.20(dd,J=8.4,1.3Hz,1H),6.99(d,J=8.2Hz,1H),6.88(s,1H),3.62(s,3H),2.39(s,3H)。13C NMR(100MHz,DMSO-d6)δ157.3,149.3,146.4,136.2,132.4,130.9,128.2,127.9,127.7,126.3,125.8,123.9,115.7,104.3,51.7,20.9。HRMS(ESI)calcd for[M+H]C13H15N2O2,m/z:231.1128,found:231.1121。
按照通用方法,得到1j-a,收率69%。
1H NMR(400MHz,CDCl3)δ7.88(d,J=1.6Hz,1H),7.63(d,J=8.8Hz,1H),7.54(d,J=8.8Hz,1H),7.46(dd,J=8.8,1.9Hz,1H),7.10(s,1H),7.06(d,J=8.8Hz,1H),6.62(s,1H),5.94(s,1H),3.79(s,3H)。13C NMR(100MHz,CDCl3)δ157.5,145.9,132.9,130.4,129.8,129.7,128.4,128.3,116.9,116.5,107.0,53.1。HRMS(ESI)calcd for[M+H]C12H12BrN2O2,m/z:295.0077,found:295.0071。
按照通用方法,得到1k-a,收率86%。
1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.04(s,2H),7.83–7.67(m,5H),7.48(t,J=7.7Hz,2H),7.35(t,J=7.3Hz,1H),7.07(d,J=8.4Hz,1H),6.94(d,J=1.6Hz,1H),3.68(d,J=26.6Hz,3H)。13C NMR(100MHz,DMSO-d6)δ157.3,147.3,140.2,133.6,133.6,129.0,128.8(2C),127.9,126.8,126.5,126.4(2C),125.2,125.0,116.1,103.8,51.8。HRMS(ESI)calcd for[M+H]C18H17N2O2,m/z:293.1285,found:293.1278。
按照通用方法,得到1l-a,收率60%。
1H NMR(500MHz,DMSO-d6)δ9.20(s,1H),7.93(s,1H),7.61(d,J=8.9Hz,2H),7.08(s,1H),6.92–6.80(m,3H),3.83(s,3H),3.41(s,3H)。13C NMR(100MHz,DMSO-d6)δ158.2,157.9,148.1,136.2,129.4,128.8,123.6,114.93,113.7,105.1,104.3,55.5,52.3。HRMS(ESI)calcd for[M+H]C13H15N2O3,m/z:247.1077,found:247.1073。
第三步:
将PCC(1.078g,6mmol)加入到1-a(5mmol)在30mL DCM中的溶液中,将混合物搅拌直到1-a完全消耗(通过TLC监测)。将反应混合物过滤,滤液减压浓缩并通过硅胶柱色谱纯化,用PE/EA(100/1-20/1)洗脱,得到相应的产物1。
按照通用方法,得到1d,收率60%。
1H NMR(500MHz,CDCl3)δ8.60(d,J=1.3Hz,1H),8.03(d,J=8.0Hz,1H),7.93–7.85(m,3H),7.66–7.55(m,2H),7.54–7.47(m,2H),7.44–7.35(m,3H),5.50(s,2H)。13C NMR(125MHz,CDCl3)δ162.1,149.4,136.2,134.5,133.1,132.6,130.0,129.5,129.2,128.9,128.8(2C),128.8(2C),128.1,127.2,115.4,69.9。HRMS(ESI)calcd for[M+H]C18H15N2O2,m/z:291.1128,found:291.1119。
按照通用方法,得到1h,收率85%。
1H NMR(400MHz,CDCl3)δ8.52(d,J=1.6Hz,1H),7.94–7.87(m,2H),7.74(d,J=9.0Hz,1H),7.22(dd,J=8.9,2.5Hz,1H),7.18(d,J=2.3Hz,1H),4.10(s,3H),3.95(s,3H)。13C NMR(100MHz,CDCl3)δ162.7,160.5,148.1,138.2,132.6,131.7,128.3,128.2,119.9,116.1,106.5,55.5,54.8。HRMS(ESI)calcd for[M+H]C13H13N2O3,m/z:245.0921,found:245.0912。
按照通用方法,得到1i,收率59%。
1H NMR(500MHz,CDCl3)δ8.56(d,J=1.2Hz,1H),7.92(d,J=8.3Hz,1H),7.89(dd,J=8.9,1.9Hz,1H),7.78(d,J=8.9Hz,1H),7.66(s,1H),7.42(dd,J=8.3,1.3Hz,1H),4.10(s,3H),2.55(s,3H)。13C NMR(125MHz,CDCl3)δ162.7,148.9,139.7,136.5,132.8,131.2,129.9,129.5,128.9,127.2,115.4,54.9,22.0。HRMS(ESI)calcd for[M+H]C13H13N2O2,m/z:229.0972,found:229.0967。
按照通用方法,得到1j,收率79%。
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.07(s,1H),7.96–7.86(m,2H),7.80(d,J=9.0Hz,1H),7.67(dd,J=8.7,1.7Hz,1H),4.11(s,3H)。13C NMR(100MHz,CDCl3)δ162.6,149.4,137.0,131.8,131.5,131.4,130.8,130.3,128.6,123.6,116.7,55.0。HRMS(ESI)calcd for[M+H]C12H10BrN2O2,m/z:292.9920,found:292.9917。
按照通用方法,得到1k,收率53%。
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.12–8.07(m,J=8.8Hz,2H),7.96–7.92(m,2H),7.85(dd,J=8.5,1.8Hz,1H),7.76–7.71(m,2H),7.54–7.48(m,2H),7.45–7.39(m,1H),4.11(s,3H)。13C NMR(100MHz,CDCl3)δ162.6,149.4,142.0,140.3,136.5,132.3,132.2,130.6,129.8,129.0(2C),128.1,127.5(2C),127.0,125.9,115.9,54.9。HRMS(ESI)calcdfor[M+H]C18H15N2O2,m/z:291.1128,found:291.1121。
按照通用方法,得到1l,收率68%。
1H NMR(500MHz,CDCl3)δ8.48(s,1H),7.83–7.73(m,3H),7.31–7.25(m,2H),4.11(s,3H),3.96(s,3H)。13C NMR(125MHz,CDCl3)δ162.7,158.6,149.9,134.5,131.7,131.1,129.5,129.3,121.9,113.2,107.7,55.5,54.9。HRMS(ESI)calcd for[M+H]C13H13N2O3,m/z:245.0921,found:245.0912。
实施例2
底物2的合成
2a,2i可以商业化购买,其他吲哚根据参考文献6~10制备。
合成2-(叔丁基)-1H-吲哚的一般方法
将相应的苯肼盐酸盐(0.72g,5mmol)和频哪酮(5mL,40mmol)、ZnCl2(2.72g,20mmol)混合,并用油浴在190℃下加热,反应混合物在该温度下保持20分钟,TLC监测反应完成后,将反应混合物冷却至室温,用水稀释,用乙酸乙酯萃取(2×50mL),将合并的有机相用水洗涤并用Na2SO4干燥,蒸发溶剂后,残余物进行硅胶柱色谱纯化,用PE/EA作为洗脱溶剂,得到产物。
2b,黄色固体,77%收率,0.73g。
1H NMR(500MHz,CDCl3)δ7.91(s,1H),7.23–7.15(m,2H),6.85(td,J=9.1,2.4Hz,1H),6.22(d,J=2.2Hz,1H),1.38(s,9H)。13C NMR(125MHz,CDCl3)δ157.9(J=231.3Hz),150.7,132.2,128.9(J=10.0Hz),110.8(J=10.0Hz),109.1(J=26.3Hz),104.8(J=23.8Hz),97.2(J=3.8Hz),31.9,30.2(3C)。HRMS(ESI)calcd for[M+H]C12H15FN,m/z:192.1183,found:192.1180。
2d,红色固体,36%收率,0.46g。
1H NMR(500MHz,CDCl3)δ8.05(s,1H),7.64(s,1H),7.25–7.16(m,2H),6.19(s,1H),1.38(s,9H)。13C NMR(125MHz,CDCl3)δ150.1,134.3,130.3,123.8,122.4,112.7,111.7,96.7,31.9,30.2(3C)。HRMS(ESI)calcd for[M+H]C12H15BrN,m/z:252.0382,found:252.0381。
2h的合成
将2,2-二甲基丁酰氯(3.5mL,0.033mol)溶于THF(10mL)中,加入邻甲苯胺(3.2mL,0.03mol)和三乙胺(2.8mL)处理,混合物回流1小时,并用乙酸乙酯稀释,有机层用食盐水洗涤并干燥(Na2SO4),并在减压下蒸发。将粗产物在0℃下溶于无水THF(20mL)中,在氮气氛下滴加n-BuLi(2.4M,在己烷中,37.5mL),混合物在0℃下搅拌1小时,并在室温下搅拌5小时,然后用乙酸乙酯(20mL)稀释并用NH4Cl水溶液(20mL)淬灭,分离有机层,用食盐水洗涤,Na2SO4干燥,减压蒸发,粗产物通过硅胶柱色谱纯化,用乙酸乙酯/己烷洗脱,得到产物。黄色固体,96%收率,5.39g。
1H NMR(400MHz,CDCl3)δ7.87(s,1H),7.54(d,J=7.7Hz,1H),7.30(d,J=7.9Hz,1H),7.15–6.97(m,2H),6.25(d,J=2.1Hz,1H),1.65(q,J=7.5Hz,2H),1.33(s,6H),0.77(t,J=7.5Hz,3H)。13C NMR(100MHz,CDCl3)δ=147.3,135.8,128.6,121.0,119.9,119.5,110.4,98.4,36.0,35.4,27.6,9.2。HRMS(ESI)calcd for[M+H]C13H18N,m/z:188.1434,found:188.1428。
第二部分:轴手性芳基吲哚的合成
实施例3
为了验证反应的可行性,如下式所示,以偶氮苯衍生物1a和2-叔丁基-吲哚2a为反应物,10mol%磷酸CP1作为催化剂,在DCM中室温反应。反应顺利进行,得到轴手性芳基吲哚3a,产率为76%,ee值为87%。可见,通过吲哚亲核进攻偶氮苯衍生物,有机催化不对称构建轴手性芳基吲哚是可行的。接下来筛选具有不同轴手性骨架和取代基的催化剂,催化剂的芳环骨架和3,3'-取代基对对映体选择性有重要影响。其中,催化剂CP4在对映选择性(92%ee)和产率(99%)方面具有最好的结果。
反应条件:在室温下,用1a(0.10mmol,1.0当量),2a(0.12mmol,1.2当量)和CP(10mol%)在二氯甲烷(2.0mL)中反应。
进一步的条件筛选,如表1所示,获得了最优的反应条件:将2a(1.1当量)加入到1a(1.0当量),2.5mol%的CP4,2.0mL甲苯溶液,室温反应,以97%ee、95%分离产率得到轴手性芳基吲哚3a。
1H NMR(500MHz,CDCl3)δ8.37(s,1H),7.82(d,J=8.9Hz,1H),7.77(d,J=7.6Hz,1H),7.37(d,J=8.0Hz,1H),7.32(d,J=8.9Hz,1H),7.30–7.19(m,3H),7.18–7.10(m,1H),7.02–6.88(m,2H),6.49(s,1H),5.77(s,1H),3.64(s,3H),1.22(s,9H)。13C NMR(125MHz,CDCl3)δ157.4,145.3,144.2,135.1,134.9,129.1,129.0,128.8,127.8,126.1,125.4,122.8,121.9,119.6,119.4,114.4,113.3,110.2,103.9,52.7,33.4,30.0(3C)。HRMS(ESI)calcd for[M+H]C24H26N3O2,m/z:388.2020,found:388.2012。HPLC分析:HPLCDAICELCHIRALCELIA,正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=10.0min,tR(minor)=11.5min,ee=97%。
表1
除非另有说明,反应在室温下、1mL溶剂中,1a的用量为0.1mmol,反应2小时,1a和2a的摩尔比为1:1.2。b:使用1,3,5-三甲氧基苯作为内标,通过粗反应混合物的1H NMR分析(CDCl3)测定产率;括号内的为分离收率。c:ee值由手性HPLC分析确定。d:反应时间为5h。e:反应在0℃进行。f:使用2mL甲苯。g:1a和2a的摩尔比为1:1.1。
由此,得到轴手性芳基吲哚的通用反应条件:室温下,将吲哚2(0.11mmol,1.1当量)加入偶氮苯衍生物1(0.1mmol,1.0当量)、CP4(1.7mg,2.5mol%)的甲苯(2.0mL)溶液。反应在室温下搅拌,直到TLC表明偶氮苯衍生物1消失。反应混合物通过硅胶柱色谱直接纯化,用PE/EA(10/1至4/1)洗脱,得到产物3,为白色固体。
外消旋化合物通过上述步骤制备,使用二苯基膦酸酯作为催化剂。
将最佳反应条件应用于各种偶氮苯衍生物1和2-叔丁基-吲哚2。
实施例4
按照通用方法,得到3b,收率95%,97%ee。
1H NMR(500MHz,CDCl3)δ8.36(s,1H),7.83(d,J=8.9Hz,1H),7.77(s,1H),7.38(d,J=8.0Hz,1H),7.32(d,J=8.9Hz,1H),7.28(d,J=7.9Hz,1H),7.26–7.19(m,2H),7.18–7.12(m,1H),6.94(d,J=3.9Hz,2H),6.43(s,1H),5.76(s,1H),4.11(s,2H),1.23(s,12H)。13C NMR(125MHz,CDCl3)δ156.9,145.3,144.2,135.1,134.9,129.1,128.9,128.8,127.8,126.1,125.4,122.7,121.9,119.6,119.4,114.4,113.2,110.1,104.0,61.7,33.4,30.0(3C),14.5。HRMS(ESI)calcd for[M+H]C25H28N3O2,m/z:402.2176,found:402.2167。HPLC分析:HPLC DAICEL CHIRALCEL IA,正己烷/异丙醇=80/20,1.0mL/min,λ=240nm,tR(major)=4.9min,tR(minor)=5.5min,ee=97%。
实施例5
按照通用方法,得到3c,收率92%,98%ee。
1H NMR(500MHz,CDCl3)δ8.34(s,1H),7.84(d,J=8.9Hz,1H),7.77(d,J=7.6Hz,1H),7.39(d,J=8.1Hz,1H),7.32(d,J=8.9Hz,1H),7.29–7.18(m,3H),7.18–7.13(m,1H),7.01–6.88(m,2H),6.07(s,1H),5.79(s,1H),1.42(s,9H),1.23(s,9H)。13C NMR(125MHz,CDCl3)δ155.8,145.2,144.3,135.1,134.9,129.2,128.8,128.7,127.8,126.0,125.3,122.6,121.8,119.6,119.4,114.2,113.5,110.1,104.1,80.7,33.4,30.0(3C),28.3(3C)。HRMS(ESI)calcd for[M+H]C27H32N3O2,m/z:430.2489,found:430.2480。HPLC分析:HPLCDAICELCHIRALCEL IB,正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=10.7min,tR(minor)=9.3min,ee=98%。
实施例6
按照通用方法,得到3d,收率93%,99%ee。
1H NMR(500MHz,CDCl3)δ8.32(s,1H),7.82(d,J=8.9Hz,1H),7.78(d,J=6.9Hz,1H),7.49–7.08(m,11H),6.96(s,2H),6.52(s,1H),5.79(s,1H),5.10(s,2H),1.21(s,9H)。13C NMR(125MHz,CDCl3)δ156.6,145.3,144.1,135.8,135.1,134.9,129.1,129.0,128.8(2C),128.5,128.3,128.2,127.8(2C),126.1,125.4,122.8,121.9,119.7,119.4,114.5,113.3,110.1,104.0,67.3,33.4,30.0(3C)。HRMS(ESI)calcd for[M+H]C30H30N3O2,m/z:464.2333,found:464.2325。HPLC分析:HPLC DAICELCHIRALCEL IB,正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=18.4min,tR(minor)=16.1min,ee=99%。
实施例7
按照通用方法,得到3e,收率94%,94%ee。
1H NMR(400MHz,CDCl3)δ8.34(s,1H),7.74(d,J=8.9Hz,1H),7.39(d,J=8.1Hz,1H),7.30(d,J=8.9Hz,1H),7.20(d,J=9.2Hz,1H),7.16(dd,J=8.1,4.5Hz,1H),7.12(d,J=2.5Hz,1H),6.99–6.89(m,3H),6.44(s,1H),5.68(s,1H),3.88(s,3H),3.65(s,3H),1.23(s,9H)。13C NMR(100MHz,CDCl3)δ157.5,155.6,145.3,142.6,135.0,130.4,129.8,129.2,127.5,127.1,122.0,119.7,119.4,118.7,115.1,114.1,110.2,106.0,104.1,55.3,52.7,33.4,30.0(3C)。HRMS(ESI)calcd for[M+H]C25H28N3O3,m/z:418.2125,found:418.2117。HPLC分析:HPLC DAICEL CHIRALCEL IA,正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=12.3min,tR(minor)=13.9min,ee=94%。
实施例8
按照通用方法,得到3f,收率94%,98%ee。
1H NMR(500MHz,CDCl3)δ8.32(s,1H),7.75(d,J=8.9Hz,1H),7.55(s,1H),7.39(d,J=8.1Hz,1H),7.29(d,J=8.9Hz,1H),7.22–7.12(m,2H),7.07(dd,J=8.6,1.4Hz,1H),6.98–6.90(m,2H),6.43(s,1H),5.72(s,1H),3.65(s,3H),2.43(s,3H),1.23(s,9H)。13C NMR(125MHz,CDCl3)δ157.4,145.3,143.5,135.0,133.1,132.2,129.2,128.4,128.1,126.9(2C),125.3,121.9,119.6,119.4,114.5,113.5,110.1,104.2,52.7,33.4,30.0(3C),21.3。HRMS(ESI)calcd for[M+H]C25H28N3O2,m/z:402.2176,found:402.2168。HPLC分析:HPLCDAICEL CHIRALCEL IB,正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=15.5min,tR(minor)=13.7min,ee=98%。
实施例9
按照通用方法,得到3g,收率90%,98%ee。
1H NMR(500MHz,CDCl3)δ8.37(s,1H),7.92(s,1H),7.73(d,J=9.0Hz,1H),7.39(d,J=8.0Hz,1H),7.33(d,J=8.9Hz,1H),7.27(dd,J=9.0,1.7Hz,1H),7.20–7.12(m,2H),7.00–6.84(m,2H),6.51(s,1H),5.78(s,1H),3.65(s,3H),1.22(s,9H)。13C NMR(125MHz,CDCl3)δ157.4,145.4,144.6,135.1,133.5,130.0,129.7,129.4,128.9,127.9,127.3,122.1,119.8,119.2,116.5,114.5,114.3,110.2,103.3,52.8,33.4,30.0(3C)。HRMS(ESI)calcd for[M+H]C24H25N3O2Br,m/z:466.1125,found:466.1117。HPLC分析:HPLC DAICELCHIRALCEL IA正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=10.6min,tR(minor)=11.9min,ee=98%。
实施例10
按照通用方法,得到3h,收率96%,98%ee。
1H NMR(500MHz,CDCl3)δ8.37(s,1H),7.99(d,J=1.5Hz,1H),7.88(d,J=8.9Hz,1H),7.69–7.64(m,2H),7.50(dd,J=8.8,1.9Hz,1H),7.46–7.38(m,3H),7.38–7.28(m,3H),7.20–7.13(m,1H),7.05–6.93(m,2H),6.48(s,1H),5.73(s,1H),3.66(s,3H),1.26(s,9H)。13C NMR(125MHz,CDCl3)δ157.4,145.4,144.3,141.2,135.4,135.1,134.2,129.2,129.2,129.1,128.7(2C),127.1(3C),126.8,126.0,125.8,122.0,119.7,119.4,114.3,113.7,110.2,103.9,52.7,33.4,30.0(3C)。HRMS(ESI)calcd for[M+H]C30H30N3O2,m/z:464.2333,found:464.2326。HPLC分析:HPLC DAICEL CHIRALCEL IB正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=19.0min,tR(minor)=17.4min,ee=98%。
实施例11
按照通用方法,得到3i,收率93%,98%ee。
1H NMR(500MHz,CDCl3)δ8.37(s,1H),7.74(d,J=8.8Hz,1H),7.67(d,J=8.9Hz,1H),7.37(d,J=8.0Hz,1H),7.19–7.11(m,2H),7.03–6.89(m,3H),6.60(d,J=1.9Hz,1H),6.46(s,1H),5.72(s,1H),3.65(s,3H),3.56(s,3H),1.25(s,9H)。13C NMR(125MHz,CDCl3)δ158.0,157.3,145.1,144.7,136.3,135.3,129.5,128.9,128.6,124.5,121.9,119.6,119.4,115.1,113.5,110.8,110.1,104.2,104.1,55.0,52.7,33.4,30.0(3C)。HRMS(ESI)calcd for[M+H]C25H28N3O3,m/z:418.2125,found:418.2116。HPLC分析:HPLC DAICELCHIRALCEL IB正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=18.4min,tR(minor)=15.4min,ee=98%。
实施例12
按照通用方法,得到3j,收率96%,97%ee。
1H NMR(500MHz,CDCl3)δ8.35(s,1H),7.84(d,J=8.9Hz,1H),7.81–7.75(m,1H),7.33(d,J=8.9Hz,1H),7.30–7.21(m,4H),6.87(t,J=8.2Hz,1H),6.59(d,J=8.3Hz,1H),6.49(s,1H),5.80(s,1H),3.66(s,3H),1.22(s,9H)。13C NMR(125MHz,CDCl3)δ158.0(J=232.5Hz),157.4,147.4,144.2,134.7,131.5,129.8(J=10.0Hz),129.1,129.0,127.9,126.3,125.1,122.9,113.7,113.3,110.7(J=8.8Hz),110.1(J=26.3Hz),104.3(J=23.8Hz),104.1(J=5.0Hz),52.8,33.5,29.9(3C)。HRMS(ESI)calcd for[M+H]C24H25N3O2F,m/z:406.1925,found:406.1918。HPLC分析:HPLC DAICEL CHIRALCEL IB正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=13.1min,tR(minor)=11.4min,ee=97%。
实施例13
按照通用方法,得到3k,收率98%,>99%ee。
1H NMR(500MHz,CDCl3)δ8.42(s,1H),7.85(d,J=8.9Hz,1H),7.79(d,J=8.1Hz,1H),7.33(d,J=8.9Hz,1H),7.31–7.20(m,4H),7.08(d,J=7.8Hz,1H),6.90(s,1H),6.50(s,1H),5.72(s,1H),3.66(s,3H),1.22(s,9H)。13C NMR(125MHz,CDCl3)δ157.5,147.0,144.2,134.8,133.4,130.3,129.2,129.0,128.0,126.3,125.3,125.1,123.0,122.2,118.8,113.4,113.3,111.3,103.9,52.8,33.4,29.9(3C)。HRMS(ESI)calcd for[M+H]C24H25N3O2Cl,m/z:422.1630,found:422.1620。HPLC分析:HPLC DAICEL CHIRALCEL IB正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=13.1min,tR(minor)=11.2min,ee>99%。
实施例14
按照通用方法,得到3l,收率98%,>99%ee。
1H NMR(500MHz,CDCl3)δ8.44(s,1H),7.85(d,J=8.9Hz,1H),7.79(d,J=7.0Hz,1H),7.33(d,J=8.8Hz,1H),7.30–7.17(m,5H),7.05(s,1H),6.51(s,1H),5.72(s,1H),3.66(s,3H),1.22(s,9H)。13C NMR(125MHz,CDCl3)δ157.6,146.9,144.2,134.8,133.7,130.9,129.2,129.0,128.0(2C),126.3,125.1,124.7,123.0,121.8,113.3,112.9,111.7,103.8,52.9,33.4,29.9(3C)。HRMS(ESI)calcd for[M+H]C24H25N3O2Br,m/z:466.1125,found:466.1116。HPLC分析:HPLC DAICEL CHIRALCEL IB正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=13.0min,tR(minor)=11.3min,ee>99%。
实施例15
按照通用方法,得到3m,收率90%,98%ee。
1H NMR(500MHz,CDCl3)δ8.25(s,1H),7.83(d,J=8.9Hz,1H),7.78(d,J=7.5Hz,1H),7.37–7.19(m,5H),6.98(d,J=8.2Hz,1H),6.72(s,1H),6.44(s,1H),5.78(s,1H),3.65(s,3H),2.26(s,3H),1.21(s,9H)。13C NMR(125MHz,CDCl3)δ157.4,145.4,144.1,135.0,133.4,129.4,129.0,128.8,128.8,127.8,126.1,125.5,123.5,122.8,118.9,114.5,113.3,109.8,103.4,52.7,33.4,30.0(3C),21.3。HRMS(ESI)calcd for[M+H]C25H28N3O2,m/z:402.2176,found:402.2168。HPLC分析:HPLC DAICEL CHIRALCEL IB正己烷/异丙醇=80/20,1.0mL/min,λ=240nm,tR(major)=8.9min,tR(minor)=5.9min,ee=98%。
实施例16
按照通用方法,得到3n,收率96%,97%ee。
1H NMR(500MHz,CDCl3)δ8.13(s,1H),7.83(d,J=8.9Hz,1H),7.77(d,J=7.7Hz,1H),7.35-7.18(m,4H),6.97(d,J=6.9Hz,1H),6.88(t,J=7.4Hz,1H),6.80(s,1H),6.45(s,1H),5.77(s,1H),3.65(s,3H),2.57(s,3H),1.25(s,9H)。13C NMR(125MHz,CDCl3)δ157.3,145.0,144.1,134.9,134.6,129.0,128.8,128.7,127.8,126.1,125.5,122.8,122.7,119.9,119.3,117.2,114.6,113.3,104.6,52.7,33.4,30.1(3C),16.6。HRMS(ESI)calcd for[M+H]C25H28N3O2,m/z:402.2176,found:402.2168。HPLC分析:HPLC DAICELCHIRALCEL IA正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=9.2min,tR(minor)=10.0min,ee=97%。
实施例17
按照通用方法,得到3o,收率97%,99%ee。
1H NMR(500MHz,CDCl3)δ8.41(s,1H),7.76(d,J=8.9Hz,1H),7.56(s,1H),7.29(t,J=8.8Hz,2H),7.16–7.03(m,3H),6.89(s,1H),6.48(s,1H),5.74(s,1H),3.65(s,3H),2.44(s,3H),1.22(s,9H)。13C NMR(125MHz,CDCl3)δ157.6,146.9,143.6,133.4,132.9,132.3,130.4,129.2,128.6,128.4,127.0,125.3,125.0,122.1(2C),118.7,113.4,111.2,104.0,52.8,33.4,29.9(3C),21.3。HRMS(ESI)calcd for[M+H]C25H27N3O2Cl,m/z:436.1786,found:436.1778。HPLC分析:HPLC DAICEL CHIRALCEL IB正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=12.4min,tR(minor)=10.6min,ee=99%。
通过X射线衍射分析测定3o的绝对构型,化合物3o的晶体结构在剑桥晶体数据中心(CCDC 1536718),数据可从www.ccdc.cam.ac.uk/conts/retrieving.html免费获得。
实施例18
按照通用方法,得到3p,收率87%,98%ee。
1H NMR(500MHz,CDCl3)δ8.25(s,1H),7.92(d,J=1.6Hz,1H),7.73(d,J=8.9Hz,1H),7.34(d,J=8.9Hz,1H),7.28(dd,J=9.0,2.2Hz,2H),7.17(d,J=9.0Hz,1H),6.99(d,J=8.1Hz,1H),6.68(s,1H),6.37(s,1H),5.78(s,1H),3.67(s,3H),2.27(s,3H),1.21(s,9H)。13C NMR(125MHz,CDCl3)δ157.4,145.5,144.5,133.5,133.3,130.0,129.7,129.3,129.2,129.0,127.8,127.3,123.6,118.7,116.5,114.6,114.2,109.9,102.8,52.7,33.3,30.0(3C),21.3。HRMS(ESI)calcd for[M+H]C25H27N3O2Br,m/z:480.1281,found:480.1276。HPLC分析:HPLC DAICEL CHIRALCEL IB正己烷/异丙醇=80/20,1mL/min,λ=240nm,tR(major)=8.7min,tR(minor)=6.1min,ee=98%。
实施例19
按照通用方法,得到3q,收率93%,98%ee。
1H NMR(500MHz,CDCl3)δ8.44(s,1H),7.93(s,1H),7.75(d,J=9.0Hz,1H),7.34(d,J=8.9Hz,1H),7.30(dd,J=8.9,1.7Hz,2H),7.15–7.04(m,2H),6.86(s,1H),6.51(s,1H),5.72(s,1H),3.65(s,3H),1.21(s,9H)。13C NMR(125MHz,CDCl3)δ157.5,147.1,144.6,133.4,133.3,130.1,130.0,129.9,129.6,128.2,127.0,125.5,122.3,118.6,116.6,114.3,113.5,111.4,103.2,52.9,33.4,29.9(3C)。HRMS(ESI)calcd for[M+H]C24H24N3O2BrCl,m/z:500.0735,found:500.0726。HPLC分析:HPLC DAICEL CHIRALCEL IB正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=13.4min,tR(minor)=11.6min,ee=98%。
实施例20
按照通用方法,得到3r,收率92%,98%ee。
1H NMR(500MHz,CDCl3)δ8.23(s,1H),7.75(d,J=8.9Hz,1H),7.56(s,1H),7.28(t,J=8.5Hz,2H),7.20(d,J=8.6Hz,1H),7.07(dd,J=8.6,1.4Hz,1H),6.98(d,J=8.1Hz,1H),6.71(s,1H),6.42(s,1H),5.73(s,1H),3.65(s,3H),2.43(s,3H),2.25(s,3H),1.22(s,9H)。13C NMR(125MHz,CDCl3)δ157.4,145.3,143.5,133.3,133.1,132.2,129.5,129.2,128.8,128.4,128.1,126.9,125.4,123.4,119.0,114.6,113.4,109.8,103.6,52.7,33.4,30.0(3C),21.3(2C)。HRMS(ESI)calcd for[M+H]C26H30N3O2,m/z:416.2333,found:416.2325。HPLC分析:HPLC DAICEL CHIRALCEL IB正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=17.6min,tR(minor)=11.2min,ee=98%。
实施例21
按照通用方法,得到3s,收率90%,88%ee。
1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.84(d,J=8.9Hz,1H),7.81–7.76(m,1H),7.40–7.29(m,3H),7.29–7.20(m,2H),7.16(t,J=7.8Hz,1H),7.04(s,1H),7.01–6.95(m,1H),6.48(s,1H),5.76(s,1H),3.64(s,3H),1.30(s,3H),0.91–0.80(m,1H),0.75–0.66(m,1H),0.48–0.41(m,1H),0.40–0.34(m,1H)。13C NMR(100MHz,CDCl3)δ157.4,144.1,141.7,135.3,134.6,129.1,128.9,128.7,127.9,126.1,125.3,122.9,122.0,119.8,119.5,113.5,113.2,110.3,105.6,52.7,24.5,14.3,13.8,13.5。HRMS(ESI)calcd for[M+H]C24H24N3O2,m/z:386.1863,found:386.1853。HPLC分析:HPLC DAICEL CHIRALCEL IA正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=12.3min,tR(minor)=14.9min,ee=88%。
实施例22
按照通用方法,得到3t,收率95%,92%ee。
1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.83(d,J=8.9Hz,1H),7.77(d,J=7.3Hz,1H),7.39(d,J=8.1Hz,1H),7.34–7.20(m,4H),7.20–7.12(m,1H),6.95(d,J=4.2Hz,2H),6.42(s,1H),5.76(s,1H),3.64(s,3H),1.70–1.56(m,2H),1.15(s,3H),1.12(s,3H),0.79(t,J=7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ157.4,144.3,144.2,135.2,135.0,129.2,129.0,128.8,127.8,126.1,125.5,122.8,121.9,119.6,119.4,114.4,113.2,110.1,105.2,52.7,37.1,36.4,27.2,26.9,9.5。HRMS(ESI)calcd for[M+H]C25H28N3O2,m/z:402.2176,found:402.2164。HPLC分析:HPLC DAICEL CHIRALCEL IA正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=10.1min,tR(minor)=11.4min,ee=92%。
实施例23
按照通用方法,得到3u,收率92%,92%ee。
1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.75(d,J=8.9Hz,1H),7.55(s,1H),7.39(d,J=8.1Hz,1H),7.28(d,J=8.9Hz,1H),7.24–7.12(m,2H),7.06(d,J=8.6Hz,1H),6.99–6.88(m,2H),6.42(s,1H),5.71(s,1H),3.64(s,3H),2.43(s,3H),1.70–1.57(m,2H),1.16(s,3H),1.12(s,3H),0.79(t,J=7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ157.5,144.2,143.5,135.2,133.1,132.2,129.2,129.2,128.3,128.1,126.9,125.4,121.9,119.5,119.4,114.5,113.4,110.1,105.3,52.7,37.0,36.4,27.2,26.9,21.3,9.5。HRMS(ESI)calcd for[M+H]C26H30N3O2,m/z:416.2333,found:416.2329。HPLC分析:HPLC DAICEL CHIRALCEL IA正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=9.7min,tR(minor)=10.7min,ee=92%。
实施例24
按照通用方法,得到3v,收率86%,95%ee。
1H NMR(400MHz,CDCl3)δ8.32(s,1H),7.75(d,J=8.8Hz,1H),7.67(d,J=8.9Hz,1H),7.38(d,J=8.1Hz,1H),7.19–7.12(m,2H),7.03–6.88(m,3H),6.61(d,J=2.4Hz,1H),6.43(s,1H),5.70(s,1H),3.64(s,3H),3.55(s,3H),1.70–1.62(m,2H),1.19(s,3H),1.14(s,3H),0.80(t,J=7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ158.0,157.4,144.7,144.0,136.3,135.4,129.5,128.9,128.6,124.5,121.9,119.5,119.4,115.3,113.5,110.8,110.1,105.5,104.2,55.0,52.7,37.1,36.5,27.3,26.7,9.7。HRMS(ESI)calcd for[M+H]C26H30N3O3,m/z:432.2282,found:432.2278。HPLC分析:HPLC DAICEL CHIRALCEL IA正己烷/异丙醇=80/20,0.5mL/min,λ=240nm,tR(major)=10.3min,tR(minor)=12.4min,ee=95%。
实施例25
3w的合成:由于采用通用条件并没有得到很好的结果,于是进行条件筛选,如表2所示。
表2
除非另有说明,反应在室温下,在1mL溶剂中用0.05mmol标准品进行,1a与2i的摩尔比为1:1.1。b:使用1,3,5-三甲氧基苯作为内标,通过粗反应混合物的1H NMR分析(CDCl3)测定产率;括号内的为分离收率。c:ee值由手性HPLC分析确定。d:在0.025M进行。e:1a与2i的摩尔比为1.5:1。f:加入40mg的分子筛。
得到最优反应条件:将2-苯基吲哚2i(0.11mmol,1.1当量)加入到偶氮苯衍生物1a(0.1mmol,1.0当量),CP14(3.5mg,5mol%)的DCM(4.0mL)中。反应在室温下搅拌,直到TLC表明偶氮苯衍生物1a消耗完。反应混合物通过硅胶柱色谱直接纯化,用PE/EA(10/1至4/1)洗脱,得到纯的产物3w,为白色固体,84%收率,80%ee。
1H NMR(400MHz,CDCl3)δ8.71(d,J=12.0Hz,1H),7.86(d,J=8.9Hz,1H),7.78(d,J=7.8Hz,1H),7.46(d,J=8.1Hz,1H),7.40–7.30(m,4H),7.28–7.20(m,2H),7.20–7.08(m,5H),7.03(t,J=7.5Hz,1H),6.36(s,1H),5.90(s,1H),3.52(d,J=76.9Hz,3H)。13C NMR(100MHz,CDCl3)δ157.5,144.3,136.4,135.7,134.0,132.1,129.5,129.4,129.3,128.8(2C),128.7,128.0,127.8,126.5,126.4,125.0,123.1,123.1,120.4,120.3,114.1,113.0,110.9,106.9,52.7。HRMS(ESI)calcd for[M+H]C26H28N3O4,m/z:408.1707,found:408.1703。HPLC分析:HPLC DAICEL CHIRALCEL IA,正己烷/异丙醇=70/30,1.0mL/min,λ=240nm,tR(major)=10.2min,tR(minor)=14.2min,ee=80%。
实施例26
放大试验:为了验证该反应的用途,在最佳反应条件下进行产物3a的制备规模合成;克规模反应可以以优异的产率(1.29g,95%)获得产物3a,并保持优异的对映选择性(97%ee),表明该反应具有工业化应用价值。
参考文献:
1.Kung,H.,K.&Kung,M.-P.Phen-naphthalene and phen-quinolinederivatives and their use for binding and imaging amyloidplaques.WO2008124812(A1)(2008).
2.Long,A.&Gurrala,S.,Reddy.Anthelmintic compounds.WO2015179414(A1)(2015).
3.L.,Webber,M.J.,Martínez,A.,De Fusco,C.&List,B.Asymmetriccatalysis on the nanoscale:The organocatalytic approach tohelicenes.Angew.Chem.Int.Ed.53,5202-5205(2014).
4.Cappoen,D.et al.Biological evaluation of diazene derivatives asanti-tubercular compounds.Eur.J.Med.Chem.74,85-94(2014).
5.Hashimoto,T.,Hirose,D.&Taniguchi,T.Catalytic aerobic oxidation ofarylhydrazides with iron phthalocyanine.Adv.Synth.Catal.357,3346-3352(2015).
6.Varma,P.P.,Sherigara,B.S.,Mahadevan,K.M.&Hulikal,V.Efficient andstraightforward synthesis of tetrahydrocarbazoles and 2,3-dimethyl indolescatalyzed by can.Synth.Commun.39,158-165(2008).
7.Cardellini,L.,Greci,L.&Stipa,P.N-nitrosodiphenylamine as analternative nitrosating agent for indoles.Synth.Commun.24,677-682(1994).
8.Cullen,M.et al.Proteasome activity enhancing compounds.WO2015073528(A1)(2015).
9.Bard,R.R.&Bunnett,J.F.Indole synthesis viasrn1reactions.J.Org.Chem.45,1546-1547(1980).
10.Pirrung,M.C.,Deng,L.,Li,Z.&Park,K.Synthesis of 2,5-dihydroxy-3-(indol-3-yl)benzoquinones by acid-catalyzed condensation of indoles with 2,5-dichlorobenzoquinone.J.Org.Chem.67,8374-8388(2002).
11.Deetz,M.J.,Fahey,J.E.&Smith,B.D.Nmr studies of hydrogen bondinginteractions with secondary amide and urea groups.J.Phys.Org.Chem.14,463-467(2001).
12.Marcovici-Mizrahi,D.,Gottlieb,H.E.,Marks,V.&Nudelman,A.On thestabilization of the syn-rotamer of amino acid carbamate derivatives byhydrogen bonding.J.Org.Chem.61,8402-8406(1996).
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何属于本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应该以权利要求的保护范围为准。
Claims (10)
1.一种有机催化合成轴手性芳基吲哚3的方法,其特征在于,以手性磷酸为催化剂,化合物1和化合物2反应:
其中,
R1为氢;
R2选自叔丁基、1-甲基环丙基、1-甲基环丁基、叔戊基、芳基、杂芳基;
R3表示任意的取代基,n表示1~4的整数,n为2以上时,所存在的2个以上的R3相同或不同;
R4选自CO2R,R为烷基或苄基;
R5表示任意的取代基,m表示1~4的整数,m为2以上时,所存在的2个以上的R5相同或不同。
2.根据权利要求1所述的方法,其特征在于:
R1为氢;
R2选自叔丁基、1-甲基环丙基、叔戊基、苯基;
R3选自氢、烷基、卤素、烷氧基、苯基;
R4选自CO2R,R为烷基或苄基;
R5选自氢、烷基、卤素、烷氧基、苯基。
3.根据权利要求2所述的方法,其特征在于:
R1为氢;
R2选自叔丁基、1-甲基环丙基、叔戊基、苯基;
R3选自氢、甲基、卤素;
R4选自CO2R,R为甲基、乙基、叔丁基或苄基;
R5选自氢、甲基、卤素、甲氧基、苯基。
4.根据权利要求1~3任意一项所述的方法,其特征在于,所述手性磷酸选自具有以下结构式的化合物:
5.根据权利要求4所述的方法,其特征在于,所述手性磷酸为具有(R)-CP4或(R)-CP14结构式的化合物。
6.根据权利要求1~3任意一项所述的方法,其特征在于,所述反应以二氯甲烷、甲苯、氯仿、二氯乙烷、乙腈、四氢呋喃、乙醚或乙酸乙酯为溶剂。
7.根据权利要求1~3任意一项所述的方法,其特征在于,所述催化剂的用量至少是1mol%。
8.根据权利要求1~3任意一项所述的方法,其特征在于,所述反应的温度≥0℃。
9.根据权利要求1~3任意一项所述的方法,其特征在于,化合物1和化合物2的摩尔比为1~1.5:1~1.5。
10.根据权利要求1~3任意一项所述的方法,其特征在于:以2.5mol%权利要求4所述的(R)-CP4为催化剂,甲苯为溶剂,化合物1和化合物2的摩尔比为1:1.1,室温反应。
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Publication number | Priority date | Publication date | Assignee | Title |
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CN113185553A (zh) * | 2021-04-26 | 2021-07-30 | 王磊 | 一种具有芳基吲哚咔唑骨架的手性磷酸化合物及其制备方法与应用 |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102030780A (zh) * | 2010-10-26 | 2011-04-27 | 浙江大学 | 一种手性螺环磷酸和制备方法及其应用 |
CN105152934A (zh) * | 2015-07-24 | 2015-12-16 | 南方科技大学 | 催化不对称合成轴手性联芳基二酚的方法 |
-
2017
- 2017-09-07 CN CN201710798870.1A patent/CN107501160B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102030780A (zh) * | 2010-10-26 | 2011-04-27 | 浙江大学 | 一种手性螺环磷酸和制备方法及其应用 |
CN105152934A (zh) * | 2015-07-24 | 2015-12-16 | 南方科技大学 | 催化不对称合成轴手性联芳基二酚的方法 |
Non-Patent Citations (2)
Title |
---|
苏亚军等: "手性磷酸在不对称反应中的应用", 《有机化学》 * |
陈小芬等: "手性磷酸催化剂在不对称合成中的应用", 《化学进展》 * |
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