CN107501163B - Method for synthesizing axial chiral aniline indole under catalysis of chiral phosphoric acid - Google Patents
Method for synthesizing axial chiral aniline indole under catalysis of chiral phosphoric acid Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 54
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 229910000147 aluminium phosphate Inorganic materials 0.000 title claims abstract description 18
- SGDSMOHDZFWNFH-UHFFFAOYSA-N NC1=CC=CC=C1.C1=CC=C2NC=CC2=C1 Chemical compound NC1=CC=CC=C1.C1=CC=C2NC=CC2=C1 SGDSMOHDZFWNFH-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 14
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- -1 methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 239000013256 coordination polymer Substances 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
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 abstract description 29
- DMLAVOWQYNRWNQ-UHFFFAOYSA-N azobenzene Chemical class C1=CC=CC=C1N=NC1=CC=CC=C1 DMLAVOWQYNRWNQ-UHFFFAOYSA-N 0.000 abstract description 15
- 125000001424 substituent group Chemical group 0.000 abstract description 7
- 238000007306 functionalization reaction Methods 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 134
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 48
- 238000005160 1H NMR spectroscopy Methods 0.000 description 44
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 42
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 42
- 238000004896 high resolution mass spectrometry Methods 0.000 description 42
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 36
- 238000004128 high performance liquid chromatography Methods 0.000 description 31
- 239000000047 product Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 101000652482 Homo sapiens TBC1 domain family member 8 Proteins 0.000 description 11
- 102100030302 TBC1 domain family member 8 Human genes 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000006254 arylation reaction Methods 0.000 description 8
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000006362 organocatalysis Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 229910001868 water Inorganic materials 0.000 description 4
- BHNHHSOHWZKFOX-UHFFFAOYSA-N 2-methyl-1H-indole Chemical compound C1=CC=C2NC(C)=CC2=C1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 239000000725 suspension Substances 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
- XSRLHGSAMGVDJU-UHFFFAOYSA-N 2-propan-2-yl-1h-indole Chemical compound C1=CC=C2NC(C(C)C)=CC2=C1 XSRLHGSAMGVDJU-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 238000010499 C–H functionalization reaction Methods 0.000 description 2
- 238000012565 NMR experiment Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-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
- 238000004296 chiral HPLC Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- LMBFVSYQZXVDAH-UHFFFAOYSA-N n-phenyl-1h-indol-2-amine Chemical class C=1C2=CC=CC=C2NC=1NC1=CC=CC=C1 LMBFVSYQZXVDAH-UHFFFAOYSA-N 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007787 solid Substances 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 1
- OXOQKRNEPBHINU-UHFFFAOYSA-N (naphthalen-2-ylamino)azanium;chloride Chemical compound Cl.C1=CC=CC2=CC(NN)=CC=C21 OXOQKRNEPBHINU-UHFFFAOYSA-N 0.000 description 1
- 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
- RFCQDOVPMUSZMN-UHFFFAOYSA-N 2-Naphthalenethiol Chemical compound C1=CC=CC2=CC(S)=CC=C21 RFCQDOVPMUSZMN-UHFFFAOYSA-N 0.000 description 1
- WVPGIDWFLXGCLA-UHFFFAOYSA-N 2-tert-butyl-1h-indole Chemical compound C1=CC=C2NC(C(C)(C)C)=CC2=C1 WVPGIDWFLXGCLA-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
- 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
- 239000007832 Na2SO4 Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 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
- 238000004458 analytical method Methods 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
- 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
- 239000006227 byproduct Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine 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
- 229940125872 compound 4d Drugs 0.000 description 1
- 230000021615 conjugation Effects 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
- 238000007333 cyanation reaction Methods 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
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution 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
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 125000001072 heteroaryl group Chemical group 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
- 125000001041 indolyl group Chemical group 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
- 125000002950 monocyclic 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
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 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
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000007017 scission Effects 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006277 sulfonation reaction Methods 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
- 230000007704 transition Effects 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000010200 validation analysis Methods 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
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a method for synthesizing axial chiral aniline indole by catalysis of chiral phosphoric acid, which comprises the following steps: reacting a compound 1 and a compound 2 by taking chiral phosphoric acid as a catalyst:
wherein R is1Is hydrogen; r2Selected from methyl, ethyl, n-propyl, isopropyl; r3Represents an optional substituent, n represents an integer of 1 to 4, and when n is 2 or more, 2 or more R's are present3The same or different; r4Selected from CO2R, CONHR ', R is alkyl or benzyl, R' is alkyl or phenyl; r5Represents an optional substituent, m represents an integer of 1 to 4, and when m is 2 or more, 2 or more R's are present5The same or different. The synthesis method is suitable for azobenzene derivatives of various esters, obtains the axial chiral aniline indole with good yield and excellent enantioselectivity, and has mild reaction conditions. The method opens up a new way for organic catalysis of asymmetric aryl functionalization.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing axial chiral aniline indole under the catalysis of chiral phosphoric acid.
Background
Arylation is the fundamental reaction of organic chemistry, and is achieved primarily by electrophilic aryl substitution or transition metal-catalyzed aryl functionalization. In electrophilic aryl substitution, aromatic rings act as nucleophiles, and many important transformations such as aromatic nitration, halogenation, sulfonation, acylation, and alkylation can be carried out by electrophilic aryl substitution. Relatively, nucleophilic substitution of aryl groups involving C-H cleavage of aryl groups has been studied rarely. In the past decade, aromatic rings have been reacted with different nucleophiles as electrophiles in many useful transformations (such as transition metal catalyzed aryl C-H activation), but organocatalytic arylations involving nucleophilic substitution of aryl groups have yet to be explored.
In this regard, Nicewicz and colleagues have pioneered the use of acridine photo-organic catalysis to produce free radical cationic intermediates for aryl C-H amination and cyanation.
Although azo groups are the directing group for a series of transition metal catalyzed aryl carbon hydrogen bond activation reactions, including halogenation, oxygenation, arylation, acylation, amination, aminoalkylation, aminocarbonylation and cyclization, organocatalytic arylation of azobenzene derivatives has not been reported. Therefore, the azo group is used as an activator and a guiding group, and the reaction with the organic catalyst is a novel and important reaction, and can provide a new path for developing asymmetric organic catalysis.
Axial chiral biaryl compounds are ubiquitous in natural products and biologically active compounds and play an important role as chiral ligands or organic catalysts. Because of the importance of this structure, the catalytic enantioselective construction of biaryl frameworks has led to interest and great progress by researchers. In sharp contrast, enantioselective synthesis of axial chiral aniline indoles still faces great challenges. Therefore, there is a need to develop novel enantioselective methods for the synthesis of axial chiral aniline indoles.
Disclosure of Invention
The inventors believe that the aromatic ring is rendered electron deficient by the introduction of an electron withdrawing functionality on the aromatic ring, which is accessible for aromatic nucleophilic substitution reactions to occur, whereas the electron withdrawing functionality may be obtained by way of hydrogen or ionic bonding of an organic catalyst with the aromatic hydrocarbon functionality. Azodicarboxylate is a common organic reagent, and is widely applied to organic synthesis, such as Mitsunobu reaction, Diels-Alder reaction, Ene reaction and the like. The participation of the chiral ligand in the organic catalytic asymmetric reaction is also widely reported, and asymmetric induction is realized through the action of chiral hydrogen bonds or chiral Bronsted acid and azo. The inventors contemplate that azobenzene derivatives, in the presence of a suitable organic catalyst, by activating the azo functional group, result in a more electron-poor N ═ N double bond, which due to the conjugation of N ═ N to the aromatic ring, can directly affect the electrical properties of the aromatic ring, rendering aromatic nucleophilic substitution susceptible to occur. It was found that naphthalene-2-thiol can react with azobenzene derivative 1a to form a biaryl thioether using phosphoric acid as a catalyst, indicating that organocatalytic nucleophilic substitution of aryl groups is reasonable and feasible.
On the basis of the organic catalytic arylation of the newly discovered azobenzene derivative, the inventor assumes that chiral phosphoric acid can effectively activate indole, improve the electrophilicity of the azobenzene derivative and the nucleophilicity of the indole, and further ensure that the aromatic nucleophilic process occurs smoothly. Specifically, azobenzene derivative 1 'and 2-substituted indole 2' undergo aryl nucleophilic substitution as shown in the following formula, to give intermediate a.
If R is1Is H and R2Is a small group, is further cyclized, and is subjected to beta-hydrogen elimination and central chirality to axial chirality conversion to form axial chiral aniline indole 4'. In this case, several challenges need to be addressed: (a) searching a stable catalyst to promote the reaction and more importantly controlling the C/N chemical selectivity of the p-azobenzene derivative; (b) searching for a chiral catalyst during nucleophilic addition to control enantiomer formation; (c) mild reaction conditions are used to avoid axial rotation, i.e. racemization.
The invention aims to construct axial chiral aniline indole by enantioselective arylation of azobenzene derivatives and 2-substituted indole catalyzed by chiral phosphoric acid.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing axial chiral aniline indole 4 by organic catalysis comprises the following specific steps: reacting a compound 1 and a compound 2 by taking chiral phosphoric acid as a catalyst:
wherein,
R1is hydrogen;
R2selected from methyl, ethyl, n-propyl, isopropyl;
R3represents an optional substituent, n represents an integer of 1 to 4, and when n is 2 or more, 2 of the substituents are presentR above3The same or different;
R4selected from CO2R, CONHR ', R is alkyl or benzyl, R' is alkyl or phenyl;
R5represents an optional substituent, m represents an integer of 1 to 4, and when m is 2 or more, 2 or more R's are present5The same or different.
In a preferred embodiment of the present invention,
R1is hydrogen;
R2selected from methyl, ethyl, isopropyl;
R3selected from hydrogen, alkyl, halogen, alkoxy, cyano, ester group;
R4selected from CO2R, CONHR ', R is alkyl or benzyl, R' is alkyl or phenyl;
R5selected from hydrogen, alkyl, halogen, alkoxy, phenyl.
In a more preferred embodiment of the present invention,
R1is hydrogen;
R2selected from methyl, isopropyl;
R3selected from hydrogen, methyl, halogen, methoxy, cyano, CO2Me；
R4Selected from CO2R, CONHR ', R is methyl, ethyl, isopropyl, tert-butyl or benzyl, R' is n-propyl or phenyl;
R5selected from hydrogen, methyl, halogen, methoxy and phenyl.
In a preferred embodiment, the chiral phosphoric acid is selected from compounds having the following structural formula:
the above list is only common chiral phosphoric acid, and experiments prove that the reaction of the invention can be catalyzed, and it can be seen that the requirements of the reaction on the kind of catalyst are not strict, therefore, chiral phosphoric acid with other structures can also catalyze the reaction of the compound 1 and the compound 2.
In a more preferred embodiment, the chiral phosphoric acid is a compound having the structural formula (R) -CP 6.
In a preferred embodiment, the reaction is carried out in dichloromethane, toluene, chloroform, dichloroethane, acetonitrile, tetrahydrofuran, diethyl ether or ethyl acetate as solvent.
The above-mentioned examples are only typical solvents, and the reaction of the present invention can be smoothly carried out in any of these solvents, and it is understood that the reaction is not critical as to the kind of the solvent, and therefore, the reaction of the present invention can be smoothly carried out in other solvents.
In a preferred embodiment, the catalyst is used in an amount of at least 0.05 mol%.
The temperature of the reaction affects the time for completion of the reaction, and the lower the temperature, the longer the time required for completion of the reaction, e.g., the temperature below 0 ℃, the reaction can also be carried out. From the viewpoint of efficiency improvement, in a preferred embodiment, the reaction temperature is 0 ℃ or higher.
The molar ratio of the compound 1 to the compound 2 can be any, and in a preferred embodiment, the molar ratio of the compound 1 to the compound 2 is 1-1.5: 1 to 1.5.
In the most preferred embodiment, 0.2 mol% (R) -CP6 is used as the catalyst, methylene chloride is used as the solvent, and the molar ratio of the compound 1 to the compound 2 is 1: 1.2, reacting at room temperature.
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "ester group" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl is as defined above and "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring contains from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms.
The invention has the following beneficial effects:
in the invention, the azo group can be used as a guide group and an activation group for organic catalysis of asymmetric arylation, the azo group not only can effectively activate an aromatic ring to carry out nucleophilic attack, but also can effectively guide aryl nucleophilic substitution, and the axial chiral aniline indole can be obtained through the aryl nucleophilic substitution of azobenzene derivatives. The azo-benzene derivative (4j-4t) has excellent enantioselectivity (mostly 99% ee) regardless of the change in the substituents on the aromatic ring of the indole ring (4a-4h) or the azobenzene derivative (4j-4 t). It is noted that 2-isopropylindole (2r) is also a suitable substrate for this transformation and the axial chiral aniline indole derivative 4i is obtained in good yield (76% yield) and excellent enantioselectivity (> 99% ee). Furthermore, the model reaction for the synthesis of 4a proceeded smoothly even at very low catalyst loadings (0.05 mol%). The method opens up a new way for organic catalysis of asymmetric aryl functionalization.
The reaction of the present invention has the following important features: (a) the organic catalysis aryl nucleophilic substitution of the azobenzene derivative as an electron-philic body is realized; (b) azo groups are used as an induction group and an activation group for organic catalysis of asymmetric arylation; (c) chiral phosphoric acid is used as an organic catalyst, and axial chiral aniline indole is obtained with good yield and excellent enantioselectivity; (d) the catalyst loading can be as low as 0.05 mol%, and the reaction conditions are mild.
Detailed Description
The present invention will be further described with reference to the following specific examples.
Unless otherwise indicated, chemicals were purchased from commercial products and were not further purified. Thin Layer Chromatography (TLC) used 60F 254 silica gel plates. The silica gel column chromatography uses Qingdao marine silica gel (particle size 0.040-0.063 mm). TLC color development was performed with UV light (254 nm).1H NMR and13c NMR was characterized by Bruker 400 MHz or 500 MHz NMR spectrometer with deuterated chloroform, deuterated acetone or deuterated DMSO as solvent and Tetramethylsilane (TMS) as internal standard. Chemical shifts are in ppm and coupling constants are in Hz. In that1In H NMR, δ represents chemical shift, s represents singlet, d represents doublet, t represents triplet, q represents quartet, p represents quintet, m represents multiplet, br represents broad. In that13In C NMR, δ represents a chemical shift. The enantiomeric excess values were determined by an Agilent chiral HPLC instrument and a column of xylonite CHIRALCEL, CHIRALPAK chromatography. High Resolution Mass Spectrometry (HRMS) was performed using a Q-exact (thermo scientific) Inc mass spectrometer instrument.
A first part: synthesis of a substrate
Example 1
Synthesis of substrate 1
Preparation of aromatic Ring-substituted beta-naphthylamines 1i-aaa (R) according to references 1, 25＝6-Me)，1k-aaa(R5＝6-Ph)，1l-aaa(R57-MeO), other β -naphthylamines are commercially available.
The first step is as follows:
NaNO was added in an ice-water bath according to reference 32(513mg, 5.76mmol) of H2A solution of O (1mL) was slowly added to a suspension of the corresponding amine (4.5mmol) in hydrochloric acid (5mL), the resulting solution was stirred in an ice-water bath for 1 hour, and SnCl was slowly added2·2H2O(3.556g15.76mol) were added to the suspension, and the resulting suspension was stirred in an ice-water bath for 3.5 hours and then filtered. Successively at 0 ℃ with H2O (4X 8mL), H at room temperature2O(1×8mL)、Et2The solid was washed with O/hexane (1: 1, 2X 4mL) and dried to give the desired product.
According to the general procedure, 1i-aa was obtained in 96% yield.
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。
According to the general procedure, 1k-aa was obtained in 95% yield.
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。
The second step is that:
the corresponding hydrazine hydrochloride (10mmol) was dissolved in CH3CN (20mL), pyridine (1.71mL, 21.2mmol) was added. The solution was cooled to 0 ℃ and chloroformate (1.04mL, 11mmol) was added dropwise with stirring, and the reaction mixture was stirred at 0 ℃ for 15 minutes and then at room temperature for 1 hour. Adding water (20mL), acidifying the obtained mixture to pH 4-6 with hydrochloric acid (6M), and obtaining the productBy CH2Cl2(5X 10mL) and the combined organic phases are successively extracted with saturated NaHCO3The solution (50mL) was washed with saturated brine (50mL), and then with Na2SO4Dry and evaporate the solvent to dryness. The crude product was purified by silica gel column chromatography eluting with PE/DCM to afford the corresponding product.
According to the general procedure, 1c-a was obtained in 78% yield.
1H NMR(400MHz,CDCl3)δ7.75–7.70(m,2H),7.67(d,J＝8.2Hz,1H),7.43–7.37(m,1H),7.32–7.26(m,1H),7.14(s,1H),7.05(dd,J＝8.8,2.0Hz,1H),6.53(s,1H),5.92(s,1H),5.05–4.92(m,1H),1.29(s,6H)。13C NMR(100MHz,CDCl3)δ156.9,145.8,134.5,129.3,129.2,127.7,126.6,126.5,123.4,115.7,107.1,69.8,22.1(2C)。HRMS(ESI)calcd for[M+H]C14H17N2O2,m/z:245.1285,found:245.1276。
According to the general procedure, 1d-a was obtained in 81% yield.
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。
According to the general procedure, 1h-a is obtained in 46% yield.
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。
According to the general procedure, 1i-a was obtained in 86% yield.
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。
According to the general procedure, 1j-a was obtained in 69% yield.
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。
According to the general procedure, 1k-a was obtained in 86% yield.
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。
According to the general procedure, 1l-a was obtained in 60% yield.
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。
The third step:
PCC (1.078g, 6mmol) is added to a solution of 1-a (5mmol) in 30mL DCM and the mixture is stirred until 1-a is completely consumed (monitored by TLC). The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE/EA (100/1-20/1) to give the corresponding product 1.
According to the general procedure, 1c was obtained in 66% yield.
1H NMR(400MHz,CDCl3)δ8.60(d,J＝1.0Hz,1H),8.04(d,J＝7.8Hz,1H),7.96–7.85(m,3H),7.68–7.56(m,2H),5.36–5.25(m,1H),1.49(d,J＝6.3Hz,6H)。13C NMR(100MHz,CDCl3)δ161.9,149.4,136.1,133.1,132.1,123.0,129.5,129.0,128.1,127.2,115.6,72.8,21.8(2C)。HRMS(ESI)calcd for[M+H]C14H15N2O2,m/z:243.1128,found:243.1119。
According to the general procedure, 1d was obtained in 60% yield.
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。
According to the general procedure, 1h was obtained in 85% yield.
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)。13CNMR(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。
According to the general procedure, 1i was obtained in 59% yield.
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。
According to the general procedure, 1j was obtained in 79% yield.
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。
According to the general procedure, 1k was obtained in 53% yield.
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。
According to the general procedure, 1l was obtained in 68% yield.
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。
Synthesis of 1f from 1b
Propylamine (180. mu.L, 2.2mmol) was added to a solution of 1b (0.456g, 2.0mmol) in 10mL EtOH and the reaction mixture was stirred and heated to 80 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE/EA (100/1-5/1) to give the desired product 1 f.
Yield 59%.1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.04(d,J＝7.9Hz,1H),7.96(dd,J＝8.9,1.8Hz,1H),7.93–7.86(m,2H),7.68–7.56(m,2H),6.56(s,1H),3.50(dd,J＝13.9,6.5Hz,2H),1.79–1.67(m,2H),1.04(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ160.7,148.7,136.0,133.2,131.9,129.9,129.5,128.9,128.1,127.2,116.0,42.4,22.8,11.4。HRMS(ESI)calcd for[M+H]C14H16N3O,m/z:242.1288,found:242.1283。
1g of synthetic reference 4.
Adding Et3N (0.85mL, 10.6mmol) was added to a solution of 2-naphthylhydrazine hydrochloride salt 1a-aa (0.974g, 5.0mmol) in 5mL of EDC, a solution of phenyl isocyanate (0.655g, 5.5mmol) in DCM (5mL) was added to the reaction mixture by syringe, the mixture was stirred for 1 hour, then filtered, the solid was washed with DCM/hexane (1: 1, 5mL) and dried to give the desired product 1 g-a. 1g was synthesized according to the method described above with a yield of 64%.
1H NMR(400MHz,CDCl3)δ8.69(d,J＝1.4Hz,1H),8.48(s,1H),8.09–8.00(m,2H),7.95–7.90(m,2H),7.79–7.74(m,2H),7.69–7.58(m,2H),7.47–7.40(m,2H),7.22(t,J＝7.4Hz,1H)。13C NMR(100MHz,CDCl3)δ157.3,148.6,136.9,136.2,133.2,132.9,130.1,129.6,129.3(2C),129.3,128.1,127.3,125.1,119.7(2C),115.9。HRMS(ESI)calcd for[M+H]C17H14N3O,m/z:276.1131,found:276.112。
Example 2
Synthesis of substrate 2
2j, 2k, 2l, 2m, 2n, 2o are commercially available and other indoles are prepared according to references 6-10.
A second part: synthesis of anilinoindoles
Example 3
When 2-methyl-indole (2j) was used as the nucleophile, the unexpected anilinoindole 4a was obtained in 73% yield, 83% ee, and the inventors next attempted to improve the yield and enantioselectivity of this transformation. Through a series of optimization experiments (table 1), the optimal reaction conditions were determined: the yield of product 4a was 87% and 99% ee catalyzed by chiral phosphoric acid CP6(0.2 mol%) at room temperature.
1H NMR(400MHz,CDCl3)δ7.85(d,J＝7.8Hz,1H),7.74(d,J＝8.2Hz,1H),7.61(d,J＝8.7Hz,1H),7.56–7.38(m,2H),7.36–7.15(m,4H),6.93–6.77(m,2H),3.83(s,3H),3.64(s,2H),2.21(s,3H)。13C NMR(100MHz,CDCl3)(two indistinguishable rotamers)δ156.0,145.9,133.5,132.8,132.2,132.0,130.1,128.8,128.5,128.2,126.0,123.4,123.0,121.5,121.2,118.6,118.3,115.1,111.3,109.6,53.6,9.5。HRMS(ESI)calcd for[M+H]C21H20N3O2346.1550 m/z, 346.1547 found. HPLC analysis HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,1.0mL/min, λ 254nm, tR(major)＝7.0min,tR(minor)＝22.0min,ee＝99％。
TABLE 1
Reaction conditions are as follows: 1a (0.10mmol) was added 2j (0.12mmol,1.2equiv.), solution of CP (2.0 mL). b: 4a and 4a1H-NMR yield was determined using dibromomethane as an internal standard. c: ee was determined by chiral HPLC. d: the isolated yields of 4a and 4a' are in parentheses.
Thus, the general reaction conditions for aniline indole are: indole 2(0.24mmol, 1.2equiv.) was added to a solution of azobenzene derivative 1(0.2mmol, 1.0 equiv.), CP6(0.2 mol%) in DCM (4.0mL) at room temperature, the reaction was stirred at room temperature until TLC indicated disappearance of azobenzene derivative 1, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE/EA to give the desired product 4.
The racemic compound was prepared by the above procedure using diphenyl phosphonate as a catalyst.
The optimum reaction conditions were applied to the reaction of various azobenzene derivatives 1 and 2-tert-butyl-indole 2.
Example 4
According to the general procedure 4b was obtained in 45% yield and 99% ee.
1H NMR(400MHz,CDCl3)δ7.65(d,J＝9.1Hz,1H),7.53(d,J＝8.8Hz,1H),7.44(d,J＝8.7Hz,2H),7.32–7.26(m,1H),7.25–7.13(m,2H),6.96(dd,J＝9.1,2.6Hz,1H),6.93–6.76(m,2H),3.87(s,8H),2.22(s,3H)。13C NMR(100MHz,CDCl3)(two indistinguishablerotamers)155.8,145.9,145.7,133.6,133.4,132.2,132.0,131.8,131.3,128.8,124.5,123.1,122.4,121.1,119.1,118.6,117.4,115.0,110.8,110.0,107.8,55.3,53.6,9.5。HRMS(ESI)calcd for[M+H]C22H22N3O3376.1656 m/z, 376.1651 found. HPLC analysis is carried out by HPLCDAICEL CHIRALCEL OD-3, 80/20 n-hexane/isopropanol, 1.0mL/min, 254nm lambda, tR(major)＝8.5min,tR(minor)＝20.2min,ee＝99％。
Example 5
According to the general procedure 4c was obtained in 74% yield and 99% ee.
1H NMR(500MHz,CDCl3)δ7.84(d,J＝7.4Hz,1H),7.75(d,J＝8.2Hz,1H),7.69–7.50(m,2H),7.42(t,J＝9.7Hz,1H),7.36–7.24(m,2H),7.14–6.91(m,2H),6.76(d,J＝7.9Hz,1H),3.82(s,3H),3.51(s,2H),2.29(s,3H),2.24–2.09(m,3H)。13C NMR(125MHz,CDCl3)(twoindistinguishable rotamers)δ156.4,155.8,143.3,143.1,133.4,133.2,132.7,132.6,132.3,130.1,129.3,129.3,128.5,128.2,127.9,127.3,125.9,123.3,123.3,123.0,122.9,121.7,121.4,118.7,118.5,115.3,115.2,111.3,109.6,53.5,20.5,9.5。HRMS(ESI)calcd for[M+H]C22H22N3O2360.1707 m/z, 360.1703 found. HPLC analysis HPLC DAICELCHIRALCEL AD-3, n-hexane/isopropanol 80/20,1.0mL/min, λ 254nm, tR(major)＝6.8min,tR(minor)＝9.6min,ee＝99％。
Example 6
According to the general procedure 4d was obtained in 69% yield and 99% ee.
1H NMR(500MHz,CDCl3)δ7.85(d,J＝6.6Hz,1H),7.72(d,J＝8.1Hz,1H),7.66–7.48(m,2H),7.48–7.25(m,5H),6.71(d,J＝7.6Hz,1H),3.84(s,3H),3.68(s,2H),2.27–2.10(m,3H)。13C NMR(125MHz,CDCl3)(two indistinguishable rotamers)δ155.8,145.2,144.9,134.4,134.2,133.7,133.5,132.7,131.5,130.1,128.6,127.9,126.1,123.6,123.6,123.2,122.8,122.7,118.4,118.2,116.5,116.4,109.9,109.6,109.3,53.6,9.5。HRMS(ESI)calcd for[M+H]C21H19BrN3O2424.0655 m/z, 424.0653 found. HPLC analysis HPLCDAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,1mL/min, λ 254nm, tR(major)＝6.2min,tR(minor)＝7.4min,ee＝99％。
Example 7
According to the general procedure 4e is obtained in 78% yield and 99% ee.
1H NMR(500MHz,CDCl3)δ7.92–7.79(m,1H),7.71(d,J＝8.1Hz,1H),7.67–7.49(m,2H),7.48–7.36(m,1H),7.36–7.27(m,2H),7.27–7.09(m,2H),6.82–6.62(m,1H),3.81(s,5H),2.27–2.06(m,3H)。13C NMR(125MHz,CDCl3)(two indistinguishable rotamers)δ155.7,144.7,144.4,133.7,132.7,131.6,131.4,130.1,128.6,127.9,126.1,123.5,122.8,122.7,118.3,118.2,116.1,116.0,110.06,109.6,53.6,9.4。HRMS(ESI)calcd for[M+H]C21H19ClN3O2380.1160 m/z, 380.1151 found. HPLC analysis HPLC DAICEL CHIRALCELAD-3, n-hexane/isopropanol 80/20,1.0mL/min, λ 254nm, tR(major)＝6.1min,tR(minor)＝12.4min,ee＝99％。
Example 8
According to the general procedure 4f was obtained in 72% yield and 99% ee.
1H NMR(400MHz,CDCl3)δ7.84(d,J＝6.2Hz,1H),7.71(d,J＝8.1Hz,1H),7.68–7.48(m,2H),7.48–7.19(m,3H),7.10–6.82(m,2H),6.75(s,1H),3.79(s,3H),3.21(s,2H),2.38–2.04(m,3H)。13C NMR(100MHz,CDCl3)(two indistinguishable rotamers)δ157.3,157.0,155.8,155.0,154.8,142.1,141.8,133.6,133.4,132.7,130.1,128.6,127.9,126.1,123.5,122.8,122.7,122.5,118.3,118.18,117.9,115.9,115.4,115.2,110.3,109.6,53.6,9.4。HRMS(ESI)calcd for[M+H]C21H19FN3O2364.1456 m/z, 364.1448 found. HPLC analysis is carried out at HPLC DAICEL CHIRALCEL OD-H, 90/10 n-hexane/isopropanol, 1.0mL/min, 254nm lambda, tR(minor)＝15.7min,tR(major)＝19.6min,ee＝99％。
Example 9
The reaction was carried out according to the general procedure at 40 ℃ with 1 mol% of CP6 giving 4g, 84% yield, 99% ee.
1H NMR(500MHz,CDCl3)δ7.88(d,J＝7.8Hz,1H),7.78–7.60(m,2H),7.60–7.42(m,3H),7.42–7.28(m,2H),7.26(s,1H),6.82(d,J＝8.3Hz,1H),4.18(d,J＝50.0Hz,2H),3.90(s,3H),2.50–2.07(m,3H)。13C NMR(125MHz,CDCl3)(two indistinguishable rotamers)δ156.0,150.2,150.0,136.1,136.0,134.0,133.8,133.2,132.9,130.1,128.7,127.7,126.2,123.8,123.6,122.5,121.4,121.2,120.4,120.29,118.2,118.0,114.3,109.7,108.6,99.9,99.4,53.6,9.4。HRMS(ESI)calcd for[M+H]C22H19N4O2371.1503 m/z, 371.1499 found. HPLC analysis HPLC DAICELCHIRALCEL AD-3, n-hexane/isopropanol 90/10,1.0mL/min, λ 254nm, tR(major)＝17.7min,tR(minor)＝20.6min,ee＝99％。
Example 10
The reaction was carried out according to the general procedure at 40 ℃ with 1 mol% of CP6 giving 4h, 78% yield, 98% ee.
1H NMR(500MHz,CDCl3)δ7.84(d,J＝7.8Hz,1H),7.76(s,1H),7.66(d,J＝8.3Hz,1H),7.60(s,1H),7.56–7.36(m,3H),7.36–7.14(m,3H),3.93(s,3H),3.85(s,2H),3.78(s,3H),2.19(s,3H)。13C NMR(125MHz,CDCl3)(two indistinguishable rotamers)δ167.6,155.9,146.1,145.9,133.5,133.3,132.8,132.8,132.3,132.1,130.4,130.1,128.6,127.9,126.4,126.1,123.6,123.5,122.8,122.8,119.5,119.1,118.3,118.2,115.7,110.3,109.7,53.6,52.1,9.5。HRMS(ESI)calcd for[M+H]C23H22N3O4404.1605 m/z, 404.1602 found. HPLC DAICEL CHIRALCEL IA, 85/15 (n-hexane/isopropanol), 1.0mL/min, 254nm lambda, tR(minor)＝18.1min,tR(major)＝20.9min,ee＝98％。
Example 11
According to the general procedure 4i was obtained in 76% yield > 99% ee.
1H NMR(400MHz,CDCl3)δ8.01–7.61(m,2H),7.60–7.44(m,2H),7.36(s,1H),7.32–7.00(m,4H),6.94–6.62(m,2H),3.85(s,2H),3.76–3.30(m,3H),3.23–2.94(m,1H),1.45–1.00(m,6H)。13C NMR(100MHz,CDCl3)δ156.9,155.8,146.2,146.0,141.3,132.9,132.8,132.6,132.4,130.2,129.0,128.6,128.5,126.1,123.6,123.4,122.8,122.7,121.9,121.7,119.0,118.8,118.4,118.1,115.0,110.4,109.5,53.6,25.8,22.4,22.2,21.0,20.8。HRMS(ESI)calcd for[M+H]C23H24N3O2374.1863 m/z, 374.1860 found. HPLC analysis HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,1.0mL/min, λ 254nm, tR(major)＝5.6min,tR(minor)＝7.7min,ee>99％。
Example 12
According to the general procedure 4j was obtained in 86% yield with 99% ee.
1H NMR(400MHz,CDCl3)δ7.84(d,J＝7.8Hz,1H),7.74(d,J＝8.1Hz,1H),7.60(d,J＝8.7Hz,1H),7.52–7.37(m,2H),7.37–7.09(m,4H),6.98–6.74(m,2H),4.27(s,2H),3.63(s,2H),2.21(s,3H),1.32(s,3H)。13C NMR(100MHz,CDCl3)(two indistinguishablerotamers)δ155.5,145.9,145.8,133.5,132.8,132.2,132.0,130.1,128.8,128.5,128.2,125.9,123.4,123.3,123.0,121.6,121.3,118.6,118.3,115.1,111.2,109.7,62.8,14.4,9.5。HRMS(ESI)calcd for[M+H]C22H22N3O2360.1707 m/z, 360.1703 found. HPLC analysis HPLCDAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,1.0mL/min, λ 254nm, tR(major)＝6.6min,tR(minor)＝22.6min,ee＝99％。
Example 13
According to the general procedure 4k is obtained in 78% yield with 99% ee.
1H NMR(400MHz,CDCl3)δ7.84(d,J＝7.8Hz,1H),7.74(d,J＝8.1Hz,1H),7.59(d,J＝8.7Hz,1H),7.43(d,J＝8.6Hz,2H),7.34–7.13(m,4H),6.94–6.75(m,2H),5.03(s,1H),3.60(s,2H),2.19(s,3H),1.33(s,6H)。13C NMR(100MHz,CDCl3)(two indistinguishablerotamers)δ155.1,145.9,145.8,133.6,133.4,132.9,132.2,132.0,130.1,128.8,128.5,128.2,125.9,123.3,123.3,123.0,121.7,121.3,118.6,118.24,115.0,111.1,109.7,70.7,21.9,9.4。HRMS(ESI)calcd for[M+H]C23H24N3O2374.1863 m/z, 374.1861 found. HPLC analysis HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,1.0mL/min, λ 254nm, tR(major)＝5.9min,tR(minor)＝14.9min,ee＝99％。
Example 14
According to the general procedure 4l was obtained in 83% yield and 98% ee.
1H NMR(500MHz,CDCl3)δ7.85(d,J＝7.7Hz,1H),7.73(d,J＝8.2Hz,1H),7.65–7.54(m,1H),7.44(s,1H),7.38–7.11(m,5H),6.95–6.75(m,2H),3.64(s,2H),2.20(s,3H),1.62–1.18(m,9H)。13C NMR(125MHz,CDCl3)(two indistinguishable rotamers)δ154.2,146.0,145.7,133.6,133.5,132.8,132.3,132.0,130.0,128.7,128.5,128.2,125.8,123.2,123.2,122.9,122.9,121.8,121.3,118.6,118.1,115.0,114.9,110.9,109.7,82.5,28.1,9.5。HRMS(ESI)calcd for[M+H]C24H26N3O2,m/z:388.2020,found:388.2013。HPLCDAICEL CHIRALCEL IA, 90/10 (n-hexane/isopropanol), 1.0mL/min, 254nm lambda, tR(minor)＝10.2min,tR(major)＝16.1min,ee＝98％。
Example 15
According to the general procedure 4m was obtained in 81% yield > 99% ee.
1H NMR(500MHz,CDCl3)δ7.83(d,J＝7.0Hz,1H),7.73(d,J＝8.2Hz,1H),7.69–7.50(m,2H),7.49–6.91(m,10H),6.91–6.58(m,2H),5.47–4.75(m,2H),3.59(s,2H),2.12(s,3H)。13C NMR(125MHz,CDCl3)(two indistinguishable rotamers)δ156.0,155.2,145.9,145.6,135.3,133.4,133.3,132.7,132.2,131.9,130.0,128.8,128.5,128.1,127.6,125.9,123.4,123.3,122.9,122.8,121.6,121.1,118.7,118.5,118.2,115.1,115.0,111.1,109.7,68.2,9.4。HRMS(ESI)calcd for[M+H]C27H24N3O2422.1863 m/z, 422.1854 found. HPLC DAICEL CHIRALCEL IA, 90/10 (n-hexane/isopropanol), 1.0mL/min, 254nm lambda, tR(major)＝23.6min,tR(minor)＝45.2min,ee>99％。
Example 16
According to the general procedure 4n is obtained in 81% yield and 98% ee.
1H NMR(400MHz,CDCl3)δ8.28–8.00(m,1H),7.92–7.72(m,2H),7.68–7.48(m,2H),7.39–7.14(m,4H),7.04–6.75(m,2H),5.01–4.41(m,1H),3.70(s,2H),3.38–2.86(m,2H),2.44–2.12(m,3H),1.51–1.32(m,2H),0.87–0.61(m,3H)。13C NMR(100MHz,CDCl3)(twoindistinguishable rotamers)δ158.1,158.1,145.9,145.6,133.6,133.3,132.6,132.5,132.1,131.9,130.2,130.1,129.0,128.9,128.6,128.5,128.1,128.0,126.2,123.9,123.7,123.6,122.9,122.8,121.2,120.9,118.9,118.8,118.7,118.4,115.2,115.2,112.1,111.9,110.05,41.7,41.7,23.2,23.2,11.0,10.99,9.5。HRMS(ESI)calcd for[M+H]C23H25N4O, m/z:373.2023 and found: 373.2015. HPLC analysis HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,1.0mL/min, λ 254nm, tR(major)＝7.1min,tR(minor)＝15.9min,ee＝98％。
Example 17
According to the general procedure 4o is obtained in 87% yield with 99% ee.
1H NMR(500MHz,DMSO-d6)δ9.74(s,1H),9.61–9.30(m,1H),9.04(s,1H),7.90(d,J＝7.9Hz,1H),7.82–7.34(m,5H),7.33–7.22(m,3H),7.19(t,J＝7.6Hz,1H),7.14–6.93(m,2H),6.90–6.78(m,1H),6.78–6.63(m,1H),4.79(s,1H),4.52(s,1H),2.16(s,3H)。13C NMR(100MHz,DMSO-d6)δ155.6,155.0,147.8,147.5,139.8,139.4,134.4,134.2,133.6,133.5,132.0,131.9,130.0,129.9,129.2,129.0,128.9,128.4,125.7,123.3,123.1,122.8,122.6,122.5,120.7,120.3,119.3,118.9,118.3,116.9,116.6,114.8,114.6,111.2,110.4,9.9。HRMS(ESI)calcd for[M+H]C26H23N4O, m/z:407.1866 and found: 407.1864. HPLC analysis HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,1.0mL/min, λ 254nm, tR(major)＝8.3min,tR(minor)＝11.8min,ee＝99％。
Example 18
According to the general procedure 4p was obtained in 72% yield with 99% ee.
1H NMR(400MHz,CDCl3)δ7.64(d,J＝9.1Hz,1H),7.50(d,J＝8.5Hz,2H),7.41(d,J＝8.4Hz,1H),7.34–7.07(m,3H),6.95(d,J＝9.1Hz,1H),6.91–6.59(m,2H),3.85(s,6H),3.36(s,2H),2.19(s,3H)。13C NMR(100MHz,CDCl3)(two indistinguishable rotamers)δ155.8,145.8,133.6,133.4,132.2,132.0,131.8,131.3,128.8,124.5,123.1,122.3,121.5,121.2,119.0,118.6,118.2,117.4,115.0,110.8,110.1,107.9,55.3,53.5,9.5。HRMS(ESI)calcd for[M+H]C22H22N3O3376.1656 m/z, 376.1652 found. HPLC analysis HPLCDAICEL CHIRALCEL AD-3, n-hexane/isopropanol 80/20,1.0mL/min, λ 254nm, tR(major)＝7.5min,tR(minor)＝20.3min,ee＝99％。
Example 19
According to the general procedure 4q was obtained in 86% yield with 99% ee.
1H NMR(400MHz,CDCl3)δ7.70–7.59(m,2H),7.59–7.44(m,2H),7.37(t,J＝8.2Hz,1H),7.30–7.13(m,2H),7.13–7.02(m,1H),6.96–6.72(m,2H),3.79(s,3H),3.15(s,2H),2.42(s,3H),2.16(s,3H)。13C NMR(100MHz,CDCl3)(two indistinguishable rotamers)δ155.9,145.9,145.7,133.3,133.2,132.7,132.4,132.2,132.0,130.3,128.7,128.0,127.7,126.1,122.8,121.6,121.3,118.6,118.2,115.0,111.0,109.6,53.5,21.4,9.4。HRMS(ESI)calcd for[M+H]C22H22N3O2360.1707 m/z, 360.1698 found. HPLCDAICEL CHIRALCEL IA, 90/10 (n-hexane/isopropanol), 1.0mL/min, 254nm lambda, tR(major)＝13.3min,tR(minor)＝32.3min,ee＝99％。
Example 20
According to the general procedure 4r was obtained in 84% yield and 99% ee.
1H NMR(500MHz,CDCl3)δ8.03(s,1H),7.78(d,J＝8.7Hz,1H),7.72–7.49(m,5H),7.48–7.34(m,3H),7.34–7.14(m,3H),6.99–6.73(m,2H),3.80(s,3H),3.30(s,2H),2.28–2.07(m,3H)。13C NMR(125MHz,CDCl3)(two indistinguishable rotamers)δ155.8,145.9,145.6,141.3,135.9,133.6,133.5,132.8,132.7,132.2,132.0,130.4,128.8,128.7,127.3,127.1,126.9,126.5,125.4,123.6,123.5,123.4,121.4,121.1,118.7,118.4,115.1,115.1,111.1,110.1,53.5,9.4。HRMS(ESI)calcd for[M+H]C27H24N3O2422.1863 m/z, 422.1852 found. HPLC DAICEL CHIRALCEL IA, 90/10 (n-hexane/isopropanol), 1.0mL/min, 254nm lambda, tR(major)＝27.3min,tR(minor)＝37.1min,ee＝99％。
Example 21
Following the general procedure 4s was obtained in 88% yield with 99% ee.
1H NMR(500MHz,CDCl3)δ7.98(s,1H),7.69–7.52(m,2H),7.52–7.39(m,2H),7.34(d,J＝8.9Hz,1H),7.28–7.09(m,2H),6.96–6.73(m,2H),3.85(s,5H),2.28–2.14(m,3H)。13CNMR(125MHz,CDCl3)(two indistinguishable rotamers)δ155.7,145.8,145.6,134.1,133.8,132.8,132.7,132.1,131.9,131.5,130.4,129.0,126.6,124.8,124.7,123.0,120.9,120.6,118.7,118.30,117.0,115.1,111.1,110.7,53.7,9.5。HRMS(ESI)calcd for[M+H]C21H19BrN3O2424.0655 m/z, 424.0648 found. HPLC analysis HPLC DAICEL CHIRALCELAD-3, n-hexane/isopropanol 80/20,1.0mL/min, λ 254nm, tR(major)＝6.7min,tR(minor)＝11.1min,ee＝99％。
Example 22
According to the general procedure 4t was obtained in 83% yield > 99% ee.
1H NMR(500MHz,CDCl3)δ7.80–7.54(m,2H),7.54–7.38(m,1H),7.35–7.12(m,3H),7.07(d,J＝2.0Hz,1H),6.94(d,J＝8.8Hz,1H),6.88–6.56(m,2H),3.79(s,3H),3.63(s,2H),3.43(s,3H),2.40–2.00(m,3H)。13C NMR(125MHz,CDCl3)(two indistinguishablerotamers)δ157.6,156.8,155.9,146.1,145.8,133.2,133.1,132.9,132.7,132.5,132.2,129.8,129.2,128.8,124.9,123.0,121.4,121.0,118.5,118.1,118.0,115.3,114.8,114.7,110.8,107.2,102.1,102.1,54.6,53.4,9.4。HRMS(ESI)calcd for[M+H]C22H22N3O3376.1656 m/z, 376.1652 found. HPLC analysis is carried out at HPLC DAICEL CHIRALCEL OD-H, 90/10 n-hexane/isopropanol, 1.0mL/min, 254nm lambda, tR(major)＝6.7min,tR(minor)＝17.9min,ee>99％。
Example 23
Validation of Structure
Rotational isomerism phenomenon: carbamates and ureas generally have both syn-and anti-rotamers (references 11, 12), and it is therefore difficult to distinguish the syn-rotamer from the anti-rotamer of the product, a phenomenon that makes NMR of the product difficult to resolve (especially13C NMR), even if various deuterated solvents were tried, the two rotamers were difficult to distinguish. To confirm the structure of the product, the inventors performed some other experiments.
1. Removal of the ester group of 4a
KOH (560mg, 10mmol) in 2mL H2The solution in O was added to a solution of 4a (34.6mg, 1mmol) in 2mL EtOH, the reaction mixture was stirred and heated to 100 deg.C, sealed and reacted for 12 h, water (5mL) was added, and then extracted with EA (2X 10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE/EA to give racemate 6 in 91% yield. NMR experiments showed product 6 to be free of rotamers.
1H NMR(400MHz,CDCl3)δ7.86(d,J＝7.7Hz,1H),7.76(d,J＝8.0Hz,1H),7.70–7.51(m,2H),7.40–7.24(m,3H),7.24–7.13(m,1H),7.01–6.75(m,2H),4.81–4.45(m,2H),3.64(s,2H),2.35(s,3H)。13C NMR(100MHz,CDCl3)δ146.0,133.7,133.2,132.3,129.7,128.6,128.5,128.2,125.7,123.0,122.9,122.3,122.2,118.4,117.9,115.0,110.2,109.6,9.9。HRMS(ESI)calcd for[M+H]C19H18N3,m/z:288.1495,found:288.1494。
2. Conversion of by-product 4a
To a solution of rac-4a' (17mg, 0.05mmol) in DCM (1.0mL) was added HCl (1M in Et250 μ L, 0.05mmol) in O), the reaction was stirred at room temperature for 2 hours.1H NMR analysis showed quantitative conversion of 4a' to 4a, indicating that the reaction scheme of the invention gives three different products (compounds 3, 4, 5) via the same intermediate.
3. Comparison of the NMR spectra at 80 ℃ and Room temperature to 4 ℃
NMR experiments were carried out in DMSO-d6 at 80 ℃ with disappearance of one of the rotamers and nuclear magnetic characterization data:
1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.85(s,1H),7.86(d,J＝8.0Hz,1H),7.70(d,J＝8.2Hz,1H),7.61(d,J＝8.8Hz,1H),7.55(d,J＝8.8Hz,1H),7.47(d,J＝8.0Hz,2H),7.37–7.23(m,3H),7.23–7.14(m,2H),7.11(d,J＝7.3Hz,1H),7.00(t,J＝7.3Hz,1H),6.86(d,J＝8.0Hz,1H),6.73(t,J＝7.3Hz,1H),4.41(s,2H),2.18(s,3H)。13C NMR(100MHz,DMSO-d6)δ155.3,147.6,139.7,134.4,133.8,132.0,130.2,129.0(2C),128.9,128.8,128.5,125.6,123.2,123.1(2C),122.6,120.9,120.2,118.9,117.0,115.0,111.2,9.8。
example 24
Amplification test: to verify the utility of the reaction, a preparative scale synthesis of product 4d was performed under optimal reaction conditions; the gram scale reaction gave product 4d in excellent yield (1.88g, 89%) and with excellent enantioselectivity (99% ee), indicating commercial applicability.
Example 25
Determination of the absolute configuration of compound 4: the compound 4d was selected and tosylated.
In a 5mL vial containing 4d (84.8mg, 0.2mmol, 99% ee), pyridine (2mL) was added followed by TsCl (53.2mg, 0.3 mmol). After the reaction mixture was stirred at room temperature for 18 hours, the reaction mixture was evaporated in vacuo and the crude product was purified by silica gel column chromatography with Et3Elution with N/PE (3/1-5/1) gave 7 in 95% ee (100.7mg, 87% yield).
1H NMR(400MHz,CDCl3)δ8.42–8.02(m,1H),7.90–7.68(m,2H),7.66–7.44(m,3H),7.43–7.23(m,3H),7.22–6.94(m,3H),6.93–6.71(m,2H),6.70–6.08(m,1H),4.05–3.52(m,3H),2.29–2.12(m,3H),2.11–1.84(m,3H)。13C NMR(100MHz,CDCl3)(twoindistinguishable rotamers)δ155.9,143.8,135.5,135.2,134.7,134.5,134.3,134.0,133.3,131.9,130.3,130.0,129.3,128.7,128.5,127.3,127.0,126.7,126.2,125.5,124.4,123.7,123.6,122.8,122.1,119.9,118.1,117.1,109.7,109.6,106.9,53.5,21.5,9.4。HRMS(ESI)calcd for[M+H]C28H25BrN3O4S, m/z:578.0744 and found: 578.0729. HPLC analysis HPLC DAICEL CHIRALCEL AD-3, n-hexane/isopropanol 85/15,1.0mL/min, λ 254nm, tR(minor)＝10.4min,tR(major)＝13.9min,ee＝95％。
The crystal structure of Compound 7 was stored in Cambridge Crystal data center (CCDC 1536614), from which data were obtainedwww.ccdc.cam.ac.uk/conts/retrieving.htmlIs obtained free of charge.
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the above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (8)
1. A method for synthesizing axial chiral aniline indole 4 by organic catalysis is characterized in that chiral phosphoric acid is used as a catalyst, and a compound 1 and a compound 2 react:
wherein,
R1is hydrogen;
R2selected from methyl, ethyl, isopropyl;
R3selected from hydrogen, alkyl, halogen, alkoxy, cyano and ester group, n represents an integer of 1-4, when n is more than 2, more than 2R exist3The same or different;
R4selected from CO2R, CONHR ', R is alkyl or benzyl, R' is alkyl or phenyl;
R5selected from hydrogen, alkyl, halogen, alkoxy and phenyl, m represents an integer of 1-4, when m is more than 2, 2 existR above5The same or different;
the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and sec-butyl;
the alkoxy is methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy or cyclohexyloxy;
the ester group is-C (O) O (alkyl), alkyl being as defined above;
the chiral phosphoric acid is selected from compounds having the following structural formula:
2. the method of claim 1, wherein:
R1is hydrogen;
R2selected from methyl, isopropyl;
R3selected from hydrogen, methyl, halogen, methoxy, cyano, CO2Me；
R4Selected from CO2R, CONHR ', R is methyl, ethyl, isopropyl, tert-butyl or benzyl, R' is n-propyl or phenyl;
R5selected from hydrogen, methyl, halogen, methoxy and phenyl.
3. The method of claim 1, wherein the chiral phosphoric acid is a compound having the structural formula (R) -CP 6.
4. The method according to any one of claims 1 to 3, wherein the reaction is carried out using methylene chloride, toluene, chloroform, dichloroethane, acetonitrile, tetrahydrofuran, diethyl ether or ethyl acetate as a solvent.
5. A process according to any one of claims 1 to 3, wherein the catalyst is present in an amount of at least 0.05 mol%.
6. A process according to any one of claims 1 to 3, wherein the temperature of the reaction is 0 ℃ or higher.
7. The method according to any one of claims 1 to 3, wherein the molar ratio of compound 1 to compound 2 is 1 to 1.5: 1 to 1.5.
8. A method according to any one of claims 1 to 3, wherein: taking 0.2 mol% (R) -CP6 as a catalyst and dichloromethane as a solvent, wherein the molar ratio of the compound 1 to the compound 2 is 1: 1.2, reacting at room temperature.
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