CN107417690A - 一种高效不对称催化合成吡咯吲哚啉的方法 - Google Patents
一种高效不对称催化合成吡咯吲哚啉的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 35
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 20
- 238000006555 catalytic reaction Methods 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 11
- 229940125782 compound 2 Drugs 0.000 claims abstract description 9
- 125000001424 substituent group Chemical group 0.000 claims abstract description 9
- 229940125904 compound 1 Drugs 0.000 claims abstract description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 16
- 150000003233 pyrroles Chemical class 0.000 claims description 16
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- -1 methoxyl group Chemical group 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 230000008859 change Effects 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 4
- 125000003118 aryl group Chemical group 0.000 abstract description 26
- DMLAVOWQYNRWNQ-UHFFFAOYSA-N azobenzene Chemical class C1=CC=CC=C1N=NC1=CC=CC=C1 DMLAVOWQYNRWNQ-UHFFFAOYSA-N 0.000 abstract description 13
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 238000007306 functionalization reaction Methods 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 60
- 238000004128 high performance liquid chromatography Methods 0.000 description 31
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical group [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 150000002475 indoles Chemical class 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000006254 arylation reaction Methods 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 0 C[Rn]CNc1c(**)cccc1 Chemical compound C[Rn]CNc1c(**)cccc1 0.000 description 6
- 230000000269 nucleophilic effect Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 5
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 150000002429 hydrazines Chemical class 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 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
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000010523 cascade reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000006362 organocatalysis Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 description 1
- PYFVEIDRTLBMHG-UHFFFAOYSA-N 2,3-dimethyl-1h-indole Chemical compound C1=CC=C2C(C)=C(C)NC2=C1 PYFVEIDRTLBMHG-UHFFFAOYSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- JBIJLHTVPXGSAM-UHFFFAOYSA-N 2-naphthylamine Chemical compound C1=CC=CC2=CC(N)=CC=C21 JBIJLHTVPXGSAM-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
- KBNIEJWIJMLUBA-UHFFFAOYSA-N CC12c3ccccc3NC1CCC2 Chemical compound CC12c3ccccc3NC1CCC2 KBNIEJWIJMLUBA-UHFFFAOYSA-N 0.000 description 1
- UGVBTQYPCQFAER-UHFFFAOYSA-N Cc(c1c2)c(C)[nH]c1ccc2Cl Chemical compound Cc(c1c2)c(C)[nH]c1ccc2Cl UGVBTQYPCQFAER-UHFFFAOYSA-N 0.000 description 1
- PMOQBVDDGHQQEM-UHFFFAOYSA-N Cc(c1c2)c(C)[nH]c1ccc2F Chemical compound Cc(c1c2)c(C)[nH]c1ccc2F PMOQBVDDGHQQEM-UHFFFAOYSA-N 0.000 description 1
- GZSTUEGIANKNTE-UHFFFAOYSA-N Cc(c1c2)c(C)[nH]c1ccc2OC Chemical compound Cc(c1c2)c(C)[nH]c1ccc2OC GZSTUEGIANKNTE-UHFFFAOYSA-N 0.000 description 1
- ZLYAWPSZMNYGSV-UHFFFAOYSA-N Cc1c(C)[nH]c2cc(C)cc(C)c12 Chemical compound Cc1c(C)[nH]c2cc(C)cc(C)c12 ZLYAWPSZMNYGSV-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- KIGXMYYGQYMICF-UHFFFAOYSA-N Diphenylphosphine Acid Chemical class C=1C=CC=CC=1P(=O)(CCCCC(=O)O)C1=CC=CC=C1 KIGXMYYGQYMICF-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- TZCCKCLHNUSAMQ-DUGSHLAESA-N NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N Chemical compound NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N TZCCKCLHNUSAMQ-DUGSHLAESA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 150000001338 aliphatic hydrocarbons 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
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012267 brine Substances 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
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000003262 carboxylic acid ester group Chemical group [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000021615 conjugation Effects 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
- 238000005336 cracking Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007423 decrease 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
- 230000008034 disappearance Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 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
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 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
- 239000010410 layer Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- UHKHUAHIAZQAED-UHFFFAOYSA-N phthalocyaninatoiron Chemical compound [Fe].N=1C2=NC(C3=CC=CC=C33)=NC3=NC(C3=CC=CC=C33)=NC3=NC(C3=CC=CC=C33)=NC3=NC=1C1=CC=CC=C12 UHKHUAHIAZQAED-UHFFFAOYSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000005839 radical cations Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up 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
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Substances [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
本发明公开了一种高效不对称催化合成吡咯吲哚啉的方法:以手性磷酸为催化剂,化合物1和化合物2反应:其中,R1选自甲基、烯丙基且R2选自甲基、乙基,或者R1,R2=‑(CH2)x‑,x表示2~6的整数;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、苯甲酰基,R为烷基;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吡咯吲哚啉,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,具体是一种高效不对称催化合成吡咯吲哚啉的方法。
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。
吡咯吲哚啉是一类重要的具有生物学活性的骨架,目前已有很多种合成方法用于该结构的不对称构建。其中,通过吲哚和亲偶极的对映选择性环化反应形成吡咯吲哚啉是最具代表性的方法之一,然而,该方法需要金属催化剂参与,底物限于3-取代的吲哚,产物是仅具有一个季碳中心的吡咯吲哚啉。因此,需要研究出新颖的对映选择性合成吡咯吲哚啉的方法。
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、R2都是烷基,进一步环化,形成吡咯吲哚啉5’。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。
本发明的目的是通过手性磷酸催化的偶氮苯衍生物与2,3-二取代吲哚的有机催化对映选择性的芳基亲核取代-环化串联反应,得到有两个相邻季碳中心的吡咯吲哚啉。
为达到上述目的,本发明采用以下技术方案:
一种有机催化合成吡咯吲哚啉5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选自甲基、烯丙基且R2选自甲基、乙基,或者R1,R2=-(CH2)x-,x表示2~6的整数;
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、苯甲酰基,R为烷基;
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选自甲基、烯丙基且R2选自甲基、乙基,或者R1,R2=-(CH2)x-,x为3或4;
R3选自氢、烷基、卤素、烷氧基、苯基;
R4选自CO2R、苯甲酰基,R为烷基;
R5选自氢、烷基、卤素、烷氧基、苯基。
在更优选的方案中,
R1选自甲基、烯丙基且R2选自甲基、乙基,或者R1,R2=-(CH2)x-,x为3或4;
R3选自氢、甲基、卤素、甲氧基;
R4选自CO2Me、苯甲酰基;
R5选自氢、甲基、卤素。
在优选的方案中,所述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)-CP3结构式的化合物。
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-20℃以下,反应也是可以进行的;相应的,温度越高,产物的ee值会有所下降。从提高效率的角度考虑,在优选的方案中,所述反应的温度≥-20℃。
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)-CP3为催化剂,二氯甲烷为溶剂,化合物1和化合物2的摩尔比为1:1.5,-20℃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。
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,通过偶氮苯衍生物与2,3-二取代吲哚通过芳基亲核取代触发的有机催化对映选择性环化反应,得到具有两个连续季碳手性中心的吡咯吲哚啉。大部分反应在24小时内完成,以几乎定量的产率、优异的对映选择性(86~97%ee)、非对映选择性(>20:1非对映体比)得到吡咯吲哚啉(5a-5o)。芳环上取代基的电子性质和位置对反应的对映选择性没有显著影响。而且,吲哚2位、3位上的取代基不限于甲基,也可以是3-烯丙基或2-乙基,分别得到预期的产物5i和5j。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)通过串联反应得到具有两个连续季碳手性中心的吡咯吲哚啉;(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
β-萘胺可以商业化购买。
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。
1m、1n、1o的合成参考文献5。
向相应的2-萘肼盐酸盐(1.0当量)在MeCN中的溶液中加入苯甲酰氯(1.1当量)和吡啶(2.2当量)。将反应混合物在室温下搅拌过夜,然后将溶液减压浓缩。悬浮液用EtOAc稀释,依次用饱和NaHCO3、食盐水洗涤。有机层用Na2SO4干燥,蒸发溶剂后,残留物用PE/EA(10/1~2/1)作为洗脱溶剂进行柱层析,得到酰肼。
将铁(II)酞菁(1.5mmol,1.5当量)加入到酰肼(1.0mmol,1.0当量)在DCM(10mL)的溶液中。将反应混合物在室温下搅拌1小时,过滤后,真空蒸发滤液。所得残余物用硅胶柱色谱纯化,通过PE/EA(30/1至10/1)洗脱,得到产物。
1m,红色固体,1.87g,两步收率72%(使用10.0mmol肼)。
1H NMR(400MHz,CDCl3)δ8.65(d,J=1.5Hz,1H),8.16–8.10(m,2H),8.06(d,J=7.8Hz,1H),8.01(dd,J=8.9,1.9Hz,1H),7.96–7.90(m,2H),7.70–7.58(m,3H),7.57–7.51(m,2H)。13C NMR(100MHz,CDCl3)δ182.0,149.8,135.9,134.5,133.2,131.9,131.1,130.6(2C),129.9,129.5,128.9,128.9(2C),128.1,127.2,115.5。HRMS(ESI)calcd for[M+H]C17H13N2O,m/z:261.1022,found:261.1021。
1n,灰色固体,184mg,两步收率54%(使用1.0mmol肼)。
1H NMR(400MHz,CDCl3)δ8.60(s,1H),8.15–8.07(m,3H),8.03(dd,J=8.9,1.9Hz,1H),7.92(d,J=8.7Hz,1H),7.85(d,J=8.9Hz,1H),7.71–7.65(m,2H),7.57–7.51(m,2H)。13C NMR(100MHz,CDCl3)δ181.8,149.9,136.7,134.6,131.7,131.3,131.3,131.0,130.8,130.6(2C),130.3,128.9(2C),128.6,123.3,116.8。HRMS(ESI)calcd for[M+H]C17H12BrN2O,m/z:339.0128,found:339.0127.
1o,灰色固体,240mg,两步收率58%(使用1.5mmol肼)。
1H NMR(400MHz,CDCl3)δ8.59(d,J=1.2Hz,1H),8.17–8.10(m,2H),8.00–7.91(m,2H),7.83(d,J=8.9Hz,1H),7.71–7.62(m,2H),7.57–7.49(m,2H),7.43(dd,J=8.3,1.2Hz,1H),2.56(s,3H)。13C NMR(100MHz,CDCl3)δ181.9,149.4,139.4,136.2,134.4,132.0,131.4,131.3,130.6(2C),129.7,129.5,128.9(2C),128.8,127.2,115.5,22.0。HRMS(ESI)calcd for[M+H]C18H15N2O,m/z:275.1179,found:275.1175。
实施例2
底物2的合成
2s,2cc,2dd可以商业化购买,其他吲哚根据参考文献6~10制备。
第二部分:吡咯吲哚啉的合成
实施例3
在10mol%催化剂CP3的存在下,用偶氮苯衍生物1m和2,3-二甲基吲哚2s进行初步筛选(表1),环加成产物吡咯吲哚啉5a的产率为95%,90%ee,随后的条件优化表明,当反应在-20℃下进行时,对映选择性可以提高到97%ee。
1H NMR(500MHz,DMSO-d6)δ10.19(s,1H),8.31(d,J=8.5Hz,1H),8.13(d,J=7.2Hz,2H),7.82(d,J=8.0Hz,1H),7.78–7.67(m,2H),7.62(ddd,J=6.7,3.9,1.2Hz,1H),7.59–7.52(m,2H),7.48(t,J=7.7Hz,1H),7.24(t,J=7.5Hz,1H),6.99(d,J=8.6Hz,1H),6.96(td,J=7.6,1.0Hz,1H),6.71(t,J=7.4Hz,1H),6.55(d,J=7.7Hz,1H),6.40(s,1H),1.82(s,3H),1.48(s,3H)。13C NMR(125MHz,DMSO-d6)δ167.7,150.5,147.1,133.9,132.9,132.2,130.4,130.3,129.7,129.3,128.8(2C),128.6(2C),127.8,126.8,125.2,122.6,122.4,121.9,117.8,112.6,108.8,97.1,57.4,20.0,19.0。HRMS(ESI)calcd for[M+H]C27H24N3O,m/z:406.1914,found:406.1913。HPLC分析:HPLC DAICEL CHIRALCEL IA,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=12.5min,tR(minor)=8.5min,ee=97%。
表1
除非另有说明,反应在1mL溶剂中、0.1mmol标准进行,反应5小时,1m和2s的摩尔比为1:1。b:分离收率。c:手性HPLC分析确定ee。d:反应时间为10h。e:1m和2s的摩尔比为1:1.5。
由此,得到吡咯吲哚啉的通用反应条件:在-20℃下,将吲哚2(0.15mmol,1.5当量)加入到1(0.1mmol,1.0当量)、CP3(1.8mg,2.5mol%)的DCM(1.0mL)溶液中,反应在-20℃下搅拌,直至TLC显示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,得到纯的产物5,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的反应。
实施例4
按照通用方法,得到5b,收率99%,95%ee。
1H NMR(500MHz,DMSO-d6)δ10.22(s,1H),8.31(d,J=6.8Hz,1H),8.12(d,J=6.3Hz,2H),7.79(dd,J=32.2,7.9Hz,2H),7.72–7.46(m,5H),7.26(d,J=6.5Hz,1H),7.00(d,J=8.2Hz,1H),6.79(d,J=7.5Hz,1H),6.51(s,1H),6.33(s,1H),1.82(s,3H),1.48(s,3H)。13C NMR(125MHz,DMSO-d6)δ167.7,156.1(J=230Hz),147.3,146.9,146.8 134.6,133.8,132.2,130.3,130.2,129.8,129.6,128.8(2C),128.6(2C),127.0,122.5(J=11.3Hz),121.2,113.8(J=22.5Hz),112.8,112.6,108.9(J=5Hz),97.7,57.7,19.8,18.9。HRMS(ESI)calcd for[M+H]C27H23FN3O,m/z:424.1820,found:424.1819。HPLC分析:HPLCDAICEL CHIRALCEL IA,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=13.5min,tR(minor)=8.6min,ee=95%。
实施例5
按照通用方法,得到5c,收率99%,95%ee。
1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.29(d,J=8.0Hz,1H),8.10(d,J=7.2Hz,2H),7.88–7.71(m,3H),7.67–7.46(m,4H),7.25(t,J=7.3Hz,1H),7.04–6.91(m,2H),6.61(s,1H),6.52(d,J=8.1Hz,1H),1.82(s,3H),1.47(s,3H)。13C NMR(100MHz,DMSO-d6)δ167.6,149.3,147.3,135.2,133.8,132.2,130.3,130.1,129.8,129.6,128.8(2C),128.5(2C),127.6,127.1,125.1,122.5,122.4,121.1,121.0,112.5,109.8,97.5,57.6,19.9,18.8。HRMS(ESI)calcd for[M+H]C27H23ClN3O,m/z:440.1524,found:440.1525。HPLC分析:HPLC DAICEL CHIRALCEL IA,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=14.0min,tR(minor)=8.6min,ee=95%。
实施例6
按照通用方法,得到5d,收率97%,95%ee。
1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.28(d,J=8.4Hz,1H),8.10(d,J=7.3Hz,2H),7.92–7.80(m,2H),7.76(d,J=8.7Hz,1H),7.62(t,J=7.3Hz,1H),7.58–7.47(m,3H),7.25(t,J=7.5Hz,1H),7.10(dd,J=8.3,1.9Hz,1H),6.97(d,J=8.6Hz,1H),6.64(s,1H),6.49(d,J=8.2Hz,1H),1.82(s,3H),1.47(s,3H)。13C NMR(100MHz,DMSO-d6)δ167.6,149.6,147.3,135.8,133.8,132.2,130.4,130.3,130.1,129.8,129.6,128.8(2C),128.5(2C),127.7,127.1,122.5,122.4,121.0,112.5,110.4,108.4,97.4,57.6,19.9,18.8。HRMS(ESI)calcd for[M+H]C27H23BrN3O,m/z:486.0999,found:486.1001。HPLC分析:HPLC DAICEL CHIRALCEL IA,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=13.1min,tR(minor)=7.8min,ee=95%。
化合物5d的晶体结构存放在剑桥晶体数据中心(CCDC 1536717),数据可从www.ccdc.cam.ac.uk/conts/retrieving.html免费获得。
实施例7
按照通用方法,得到5e,收率99%,96%ee。
1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),8.31(d,J=8.4Hz,1H),8.10(d,J=7.3Hz,2H),7.82(d,J=8.1Hz,1H),7.74(d,J=8.6Hz,1H),7.67–7.44(m,5H),7.24(t,J=7.4Hz,1H),6.97(d,J=8.6Hz,1H),6.77(d,J=7.7Hz,1H),6.44(d,J=7.8Hz,1H),6.19(s,1H),2.26(s,3H),1.79(s,3H),1.44(s,3H)。13C NMR(100MHz,DMSO-d6)δ167.6,148.2,147.2,133.9,133.2,132.1,130.4,130.3,129.7,129.2,128.8(2C),128.5(2C),128.2,126.8,126.4,125.8,122.6,122.3,121.9,112.6,108.8,97.3,57.4,21.2,20.2,18.9。HRMS(ESI)calcd for[M+H]C28H26N3O,m/z:420.2070,found:420.2069。HPLC分析:HPLC DAICELCHIRALCEL IB,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=8.5min,tR(minor)=12.0min,ee=96%。
实施例8
按照通用方法,得到5f,收率99%,93%ee。
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.33(d,J=7.8Hz,1H),8.12(d,J=7.3Hz,2H),7.82(d,J=8.1Hz,1H),7.75(d,J=8.7Hz,1H),7.66–7.45(m,4H),7.39(s,1H),7.24(t,J=7.4Hz,1H),7.00(d,J=8.6Hz,1H),6.59(dd,J=8.4,2.2Hz,1H),6.48(d,J=8.3Hz,1H),6.02(s,1H),3.73(s,3H),1.82(s,3H),1.47(s,3H)。13C NMR(100MHz,DMSO-d6)δ167.6,152.7,147.3,144.4,134.4,133.9,132.1,130.4,130.3,129.7,129.3,128.8(2C),128.5(2C),128.3,126.9,122.6,122.4,121.7,112.7,112.5,109.1,97.5,57.7,56.1,20.0,18.9。HRMS(ESI)calcd for[M+H]C28H26N3O2,m/z:436.2020,found:436.2021。HPLC分析:HPLC DAICEL CHIRALCEL IA,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=12.5min,tR(minor)=9.0min,ee=93%。
实施例9
按照通用方法,得到5g,收率99%,94%ee。
1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.19(d,J=8.5Hz,1H),8.03(d,J=7.3Hz,2H),7.82(d,J=8.2Hz,1H),7.73(d,J=8.6Hz,1H),7.65–7.43(m,4H),7.23(t,J=7.4Hz,1H),6.91(d,J=8.6Hz,1H),6.32–6.21(m,3H),2.22(s,3H),2.14(s,3H),1.71(s,3H),1.35(s,3H)。13C NMR(100MHz,DMSO-d6)δ167.5,150.7,148.3,136.9,133.9,133.8,132.1,131.4,129.8,129.7,129.0,128.7(2C),128.6,128.5(2C),126.5,123.3,122.3,121.9,121.2,112.0,108.3,100.1,57.6,21.4,20.3,20.1,15.8。HRMS(ESI)calcd for[M+H]C29H28N3O,m/z:434.2227,found:434.2228。HPLC分析:HPLC DAICEL CHIRALCEL IB,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=11.3min,tR(minor)=21.0min,ee=94%。
实施例10
按照通用方法,得到5h,收率94%,96%ee。
1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.30(d,J=8.1Hz,1H),8.11(d,J=7.3Hz,2H),7.81(d,J=8.1Hz,1H),7.73(d,J=8.6Hz,1H),7.68–7.43(m,5H),7.23(t,J=7.4Hz,1H),6.98(d,J=8.6Hz,1H),6.80(d,J=7.3Hz,1H),6.63(t,J=7.3Hz,1H),6.02(s,1H),2.10(s,3H),1.80(s,3H),1.48(s,3H)。13C NMR(100MHz,DMSO-d6)δ167.7,148.8,147.1,133.9,132.4,132.1,130.4,130.2,129.7,129.2,128.8,128.8(2C),128.6(2C),126.8,122.6,122.5,122.3,121.9,118.1,117.9,112.4,97.0,57.6,20.3,18.7,17.3。HRMS(ESI)calcd for[M+H]C28H26N3O,m/z:420.2070,found:420.2071。HPLC分析:HPLC DAICELCHIRALCEL IB,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=7.4min,tR(minor)=17.7min,ee=96%。
实施例11
按照通用方法,得到5i,收率85%,89%ee。
1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),8.25(d,J=8.5Hz,1H),8.11(d,J=7.2Hz,2H),7.80(d,J=7.9Hz,2H),7.74(d,J=8.7Hz,1H),7.65–7.59(m,1H),7.58–7.52(m,2H),7.45(t,J=7.4Hz,1H),7.22(t,J=7.5Hz,1H),7.04–6.90(m,2H),6.70(t,J=7.3Hz,1H),6.52(d,J=7.7Hz,1H),6.37(s,1H),5.76–5.66(m,1H),5.02(dd,J=15.5Hz,1H),4.81(d,J=10.5Hz,1H),3.58(dd,J=15.0,6.9Hz,1H),2.89(d,J=15.5,4.9Hz,1H),1.54(s,3H)。13C NMR(100MHz,DMSO-d6)δ167.5,150.6,147.9,135.0,133.9,132.1,130.5,130.2,129.7,129.5,128.7(2C),128.5(2C),128.1,128.0,127.8,126.7,125.4,122.7,122.3,119.8,117.6,112.6,108.7,97.0,60.6,37.4,19.3。HRMS(ESI)calcd for[M+H]C29H26N3O,m/z:432.2070,found:432.2071。HPLC分析:HPLC DAICEL CHIRALCEL IB,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=8.8min,tR(minor)=12.1min,ee=89%。
实施例12
按照通用方法,得到5j,收率99%,91%ee。
1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.27(d,J=8.5Hz,1H),8.10(d,J=7.2Hz,2H),7.81(d,J=8.1Hz,1H),7.77–7.72(m,2H),7.62(t,J=7.3Hz,1H),7.58–7.51(m,2H),7.45(t,J=7.4Hz,1H),7.23(t,J=7.4Hz,1H),7.00–6.89(m,2H),6.67(t,J=7.4Hz,1H),6.55–6.47(m,2H),2.02(dt,J=11.2,7.3Hz,2H),1.86(s,3H),0.81(t,J=7.4Hz,3H)。13C NMR(100MHz,DMSO-d6)δ167.7,151.5,147.0,133.9,133.0,132.1,130.5,129.9,129.7,129.4,128.7(2C),128.6(2C),127.8,126.7,124.4,122.6,122.6,122.4,117.3,113.0,107.6,99.0,57.5,26.9,19.1,8.9。HRMS(ESI)calcd for[M+H]C28H26N3O,m/z:420.2070,found:420.2069。HPLC分析:HPLC DAICEL CHIRALCEL IB,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=8.6min,tR(minor)=15.9min,ee=91%。
实施例13
按照通用方法,得到5k,收率95%,92%ee。
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.23–8.05(m,3H),7.85–7.77(m,2H),7.75(d,J=8.6Hz,1H),7.62(t,J=7.2Hz,1H),7.55(t,J=7.4Hz,2H),7.42(t,J=7.5Hz,1H),7.22(t,J=7.4Hz,1H),7.05(d,J=8.6Hz,1H),6.97(t,J=7.5Hz,1H),6.76(t,J=7.3Hz,1H),6.55(d,J=7.6Hz,1H),6.27(s,1H),3.01(s,1H),2.28(d,J=13.0Hz,1H),1.77–1.55(m,3H),1.55–1.45(m,1H),1.44–1.31(m,1H),1.30–1.10(m,1H)。13C NMR(100MHz,DMSO-d6)δ167.7,151.4,146.6,133.8,132.1,130.8,130.4,130.1,129.6,128.9,128.7(2C),128.6(2C),127.9,126.6,125.0,123.3,122.8,122.4,117.9,113.1,109.4,95.4,56.7,32.1,30.5,21.1,20.8。HRMS(ESI)calcd for[M+H]C29H26N3O,m/z:432.2070,found:432.2067。HPLC分析:HPLC DAICEL CHIRALCEL IB,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=9.5min,tR(minor)=13.4min,ee=92%。
实施例14
按照通用方法,得到5l,收率98%,96%ee。
1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),8.22(d,J=8.4Hz,1H),8.05(d,J=7.2Hz,2H),7.84(d,J=8.1Hz,1H),7.72(d,J=8.7Hz,1H),7.67–7.51(m,5H),7.28(t,J=7.4Hz,1H),7.00–6.89(m,2H),6.65–6.52(m,3H),2.71–2.60(m,1H),2.49–2.32(m,2H),2.12–2.01(m,1H),1.91–1.80(m,1H),1.80–1.68(m,1H)。13C NMR(100MHz,DMSO-d6)δ167.4,151.6,147.6,134.0,133.5,132.3,129.9,129.9,129.6,129.1,128.9(2C),128.4(2C),128.1,127.2,124.7,123.4,122.7,122.5,118.2,112.3,109.4,104.2,67.6,42.2,38.0,26.4。HRMS(ESI)calcd for[M+H]C28H24N3O,m/z:418.1914,found:418.1910。HPLC分析:HPLCDAICEL CHIRALCEL INA,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=14.7min,tR(minor)=8.0min,ee=96%。
实施例15
按照通用方法,得到5m,收率98%,86%ee。
1H NMR(500MHz,DMSO-d6)δ9.19(s,1H),8.25(d,J=5.3Hz,1H),7.81(d,J=8.1Hz,1H),7.79–7.69(m,2H),7.46(t,J=7.3Hz,1H),7.23(t,J=7.5Hz,1H),6.97(d,J=7.0Hz,1H),6.93(t,J=7.6Hz,1H),6.69(s,1H),6.49(d,J=7.2Hz,1H),6.16(s,1H),3.73(s,3H),1.74(s,3H),1.41(s,3H)。13C NMR(125MHz,DMSO-d6)δ158.0,150.5,147.1,132.4,130.4,130.2,129.7,129.4,127.8,126.8,125.3,122.6,122.4,121.6,117.7,112.5,108.8,96.5,57.1,52.4,19.5,18.9。HRMS(ESI)calcd for[M+H]C22H22N3O2,m/z:360.1707,found:360.1703。HPLC分析:HPLC DAICEL CHIRALCEL IA,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=7.9min,tR(minor)=11.0min,ee=86%。
实施例16
按照通用方法,得到5n,收率96%,97%ee。
1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.25(d,J=6.0Hz,1H),8.20–8.02(m,3H),7.83–7.47(m,6H),7.10–6.87(m,2H),6.69(s,1H),6.53(d,J=4.0Hz,1H),6.43(s,1H),1.78(s,3H),1.43(s,3H)。13C NMR(100MHz,DMSO-d6)δ167.6,150.3,147.7,133.8,132.7,132.2,131.5,131.4,129.6,128.8(2C),128.7,128.5(2C),128.2,127.9,125.0,124.9,122.2,117.9,115.0,113.7,108.8,97.1,57.3,20.1,18.9。HRMS(ESI)calcd for[M+H]C27H23BrN3O,m/z:486.0999,found:486.0998。HPLC分析:HPLC DAICEL CHIRALCEL INA,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=12.5min,tR(minor)=10.2min,ee=97%。
实施例17
按照通用方法,得到5o,收率99%,94%ee。
1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.21(d,J=8.3Hz,1H),8.10(d,J=7.2Hz,2H),7.70(s,1H),7.67–7.50(m,5H),7.31(d,J=8.3Hz,1H),7.00–6.88(m,2H),6.69(t,J=7.1Hz,1H),6.53(d,J=7.4Hz,1H),6.37(s,1H),2.39(s,3H),1.79(s,3H),1.45(s,3H)。13C NMR(100MHz,DMSO-d6)δ167.6,150.4,146.5,133.9,132.9,132.1,131.2,130.6,129.0,128.7(2C),128.5(3C),128.4,128.0,127.8,125.1,122.6,122.0,117.7,112.7,108.8,97.0,57.4,21.4,20.0,19.0。HRMS(ESI)calcd for[M+H]C28H26N3O,m/z:420.2070,found:420.2066。HPLC分析:HPLC DAICEL CHIRALCEL INA,正己烷/异丙醇=80/20,1.0mL/min,λ=254nm,tR(major)=11.2min,tR(minor)=8.2min,ee=94%。
实施例18
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5a的制备规模合成;反应性、产率和立体选择性没有变化,表明该反应具有工业化应用价值。
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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吡咯吲哚啉5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选自甲基、烯丙基且R2选自甲基、乙基,或者R1,R2=-(CH2)x-,x表示2~6的整数;
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、苯甲酰基,R为烷基;
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选自甲基、烯丙基且R2选自甲基、乙基,或者R1,R2=-(CH2)x-,x为3或4;
R3选自氢、烷基、卤素、烷氧基、苯基;
R4选自CO2R、苯甲酰基,R为烷基;
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选自甲基、烯丙基且R2选自甲基、乙基,或者R1,R2=-(CH2)x-,x为3或4;
R3选自氢、甲基、卤素、甲氧基;
R4选自CO2Me、苯甲酰基;
R5选自氢、甲基、卤素。
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)-CP3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≥-20℃。
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)-CP3为催化剂,二氯甲烷为溶剂,化合物1和化合物2的摩尔比为1:1.5,-20℃反应。
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