CN113801054A - Preparation method of 3-alkyl-3-hydroxyindole-2-ketone and derivatives thereof and products thereof - Google Patents
Preparation method of 3-alkyl-3-hydroxyindole-2-ketone and derivatives thereof and products thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 122
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 108
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 96
- 239000003960 organic solvent Substances 0.000 claims description 71
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 64
- 239000012046 mixed solvent Substances 0.000 claims description 33
- 238000004587 chromatography analysis Methods 0.000 claims description 32
- 239000003208 petroleum Substances 0.000 claims description 32
- -1 trifluoromethyl Oxygen Chemical compound 0.000 claims description 32
- 239000003480 eluent Substances 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 239000008096 xylene Substances 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000011097 chromatography purification Methods 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 abstract description 44
- 238000000034 method Methods 0.000 abstract description 22
- 230000008569 process Effects 0.000 abstract description 13
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 239000000758 substrate Substances 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 239000003054 catalyst Substances 0.000 abstract description 8
- 150000002085 enols Chemical class 0.000 abstract description 5
- 239000000654 additive Substances 0.000 abstract description 3
- 230000000996 additive effect Effects 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 150000002894 organic compounds Chemical class 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 110
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 30
- 238000004896 high resolution mass spectrometry Methods 0.000 description 28
- 230000001678 irradiating effect Effects 0.000 description 28
- 239000007787 solid Substances 0.000 description 26
- CKGKXGQVRVAKEA-UHFFFAOYSA-N (2-methylphenyl)-phenylmethanone Chemical compound CC1=CC=CC=C1C(=O)C1=CC=CC=C1 CKGKXGQVRVAKEA-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 19
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 10
- 239000000376 reactant Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 230000005281 excited state Effects 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 238000004293 19F NMR spectroscopy Methods 0.000 description 4
- MOJHIZLOKWRPIS-UHFFFAOYSA-N 6-methoxy-1h-indole-2,3-dione Chemical compound COC1=CC=C2C(=O)C(=O)NC2=C1 MOJHIZLOKWRPIS-UHFFFAOYSA-N 0.000 description 4
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- 108010016626 Dipeptides Proteins 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 238000005882 aldol condensation reaction Methods 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 238000000295 emission spectrum Methods 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
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- 239000007858 starting material Substances 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- UYSQHMXRROFKRN-UHFFFAOYSA-N (2,4-dimethylphenyl)-phenylmethanone Chemical compound CC1=CC(C)=CC=C1C(=O)C1=CC=CC=C1 UYSQHMXRROFKRN-UHFFFAOYSA-N 0.000 description 2
- YALAPASTOMTKIH-UHFFFAOYSA-N (3-bromophenyl)-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C1=CC=CC(Br)=C1 YALAPASTOMTKIH-UHFFFAOYSA-N 0.000 description 2
- JSTTZOQOYJTDGW-UHFFFAOYSA-N (3-chlorophenyl)-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C1=CC=CC(Cl)=C1 JSTTZOQOYJTDGW-UHFFFAOYSA-N 0.000 description 2
- NCAJNMLZORDDCH-UHFFFAOYSA-N (4-fluorophenyl)-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C1=CC=C(F)C=C1 NCAJNMLZORDDCH-UHFFFAOYSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- OEUGDMOJQQLVAZ-UHFFFAOYSA-N 5-Iodoisatin Chemical compound IC1=CC=C2NC(=O)C(=O)C2=C1 OEUGDMOJQQLVAZ-UHFFFAOYSA-N 0.000 description 2
- DMHGXMPXHPOXBF-UHFFFAOYSA-N 5-Methoxyisatin Chemical compound COC1=CC=C2NC(=O)C(=O)C2=C1 DMHGXMPXHPOXBF-UHFFFAOYSA-N 0.000 description 2
- HVPQMLZLINVIHW-UHFFFAOYSA-N 6-bromo-1h-indole-2,3-dione Chemical compound BrC1=CC=C2C(=O)C(=O)NC2=C1 HVPQMLZLINVIHW-UHFFFAOYSA-N 0.000 description 2
- UEHZKEABUOAZSH-UHFFFAOYSA-N 7-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=CC2=C1NC(=O)C2=O UEHZKEABUOAZSH-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 229960001404 quinidine Drugs 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- JVRBCPIWWKGJJO-UHFFFAOYSA-N (3-fluoro-2-methylphenyl)-phenylmethanone Chemical compound CC1=C(F)C=CC=C1C(=O)C1=CC=CC=C1 JVRBCPIWWKGJJO-UHFFFAOYSA-N 0.000 description 1
- POHRRVPQMJGTKX-UHFFFAOYSA-N (4-bromophenyl)-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C1=CC=C(Br)C=C1 POHRRVPQMJGTKX-UHFFFAOYSA-N 0.000 description 1
- VPJOUHYHNNHYSP-UHFFFAOYSA-N (4-chloro-2-methylphenyl)-phenylmethanone Chemical compound CC1=CC(Cl)=CC=C1C(=O)C1=CC=CC=C1 VPJOUHYHNNHYSP-UHFFFAOYSA-N 0.000 description 1
- ANUVSUAAQDMRJQ-UHFFFAOYSA-N (5-bromo-2-methylphenyl)-phenylmethanone Chemical compound CC1=CC=C(Br)C=C1C(=O)C1=CC=CC=C1 ANUVSUAAQDMRJQ-UHFFFAOYSA-N 0.000 description 1
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- CHRLZPVKOWNUHY-UHFFFAOYSA-N 1-(cyclopropylmethyl)indole-2,3-dione Chemical compound C12=CC=CC=C2C(=O)C(=O)N1CC1CC1 CHRLZPVKOWNUHY-UHFFFAOYSA-N 0.000 description 1
- SIISFRLGYDVIRG-UHFFFAOYSA-N 1-benzylindole-2,3-dione Chemical compound C12=CC=CC=C2C(=O)C(=O)N1CC1=CC=CC=C1 SIISFRLGYDVIRG-UHFFFAOYSA-N 0.000 description 1
- NUXYYWOWNFEMNH-UHFFFAOYSA-N 4,7-dichloro-1h-indole-2,3-dione Chemical compound ClC1=CC=C(Cl)C2=C1NC(=O)C2=O NUXYYWOWNFEMNH-UHFFFAOYSA-N 0.000 description 1
- ITRAKBJPMLKWIW-UHFFFAOYSA-N 4-Bromoisatin Chemical compound BrC1=CC=CC2=C1C(=O)C(=O)N2 ITRAKBJPMLKWIW-UHFFFAOYSA-N 0.000 description 1
- DKAVQCARZCYRIS-UHFFFAOYSA-N 4-bromo-5-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=C2NC(=O)C(=O)C2=C1Br DKAVQCARZCYRIS-UHFFFAOYSA-N 0.000 description 1
- HFZSCCJTJGWTDZ-UHFFFAOYSA-N 5,7-dimethyl-1h-indole-2,3-dione Chemical compound CC1=CC(C)=CC2=C1NC(=O)C2=O HFZSCCJTJGWTDZ-UHFFFAOYSA-N 0.000 description 1
- MBVCESWADCIXJN-UHFFFAOYSA-N 5-Bromoisatin Chemical compound BrC1=CC=C2NC(=O)C(=O)C2=C1 MBVCESWADCIXJN-UHFFFAOYSA-N 0.000 description 1
- XHDJYQWGFIBCEP-UHFFFAOYSA-N 5-Chloro-1H-indole-2,3-dione Chemical compound ClC1=CC=C2NC(=O)C(=O)C2=C1 XHDJYQWGFIBCEP-UHFFFAOYSA-N 0.000 description 1
- GKODDAXOSGGARJ-UHFFFAOYSA-N 5-Fluoroisatin Chemical compound FC1=CC=C2NC(=O)C(=O)C2=C1 GKODDAXOSGGARJ-UHFFFAOYSA-N 0.000 description 1
- VAJCSPZKMVQIAP-UHFFFAOYSA-N 5-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=C2NC(=O)C(=O)C2=C1 VAJCSPZKMVQIAP-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- ZICYPCXUDCAEGR-UHFFFAOYSA-N OC(CC(C=CC=C1)=C1C(C1=CC=CC=C1)=O)(C1=CC=CC=C1N1)C1=O Chemical compound OC(CC(C=CC=C1)=C1C(C1=CC=CC=C1)=O)(C1=CC=CC=C1N1)C1=O ZICYPCXUDCAEGR-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 238000005837 enolization reaction Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000007557 optical granulometry Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052706 scandium Inorganic materials 0.000 description 1
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to a preparation method of 3-alkyl-3-hydroxyindole-2-ketone and derivatives thereof and products thereof, belonging to the technical field of organic compound preparation. The invention relates to a preparation method of 3-alkyl-3-hydroxyindole-2-ketone and derivatives thereof, which realizes the high-efficiency synthesis of the 3-alkyl-3-hydroxyindole-2-ketone and the derivatives thereof, does not need any catalyst or additive, and in the reaction, a substrate compound II undergoes an enol interconversion process under the irradiation of ultraviolet light to generate a hydroxyphthaline intermediate which is then captured by cheap and easily obtained isatin to obtain a corresponding target product. The reaction of the preparation method has good functional group tolerance and wide substrate range, can synthesize various 3-alkyl-3-hydroxyindole-2-ketone compounds and derivatives thereof, has high yield, and shows huge synthesis potential in organic synthesis.
Description
Technical Field
The invention belongs to the technical field of organic compound preparation, and relates to a preparation method of 3-alkyl-3-hydroxyindole-2-ketone and derivatives thereof and products thereof.
Background
The 3, 3-disubstituted indol-2-one structure widely exists in natural products and drug molecules. 3-alkyl-3-hydroxyindol-2-one derivatives, which are important 3, 3-disubstituted indol-2-ones, have received extensive attention from organic chemists and in recent years a great deal of effort has been devoted to the development of efficient synthetic methods. To date, one of the most straightforward methods for efficiently preparing 3-alkyl-3-hydroxyindol-2-one compounds is by intermolecular aldol-type reactions of readily available isatin with ketones or aldehydes. As early as 2005, Tomasini et al have reported dipeptide-catalyzed aldol condensation of acetone with N-alkyl isatin and effectively utilized this method to synthesize the natural product (R) -Convolutamydine (shown as A in FIG. 1). Mechanistically, dipeptide catalysts activate ketones by forming enamine intermediates. In another study, Zhao et al achieved the aldol condensation of ketones and isatin by an enolization process (shown as B in FIG. 1) using quinidine thiourea as a catalyst. In addition, many groups have successfully achieved a direct aldol-type reaction of metal catalyzed (e.g., copper, iridium, scandium, etc.) isatin and nucleophiles (as shown in C in fig. 1). Although many synthetic strategies have been developed to synthesize such structures starting from isatin, the nucleophiles used are all commonly found aldehydes, ketones, indoles, etc. In view of the importance of the structure of 3-alkyl-3-hydroxyindol-2-ones, there is a need to develop more types of nucleophiles to enrich the reaction types for synthesizing such compounds and to obtain structurally diverse products.
Photoenolized intermediates (hydroxyphthaline reactive intermediates), were recognized by scientists as early as 60 s in the 20 th century. Research shows that the intermolecular trapping process of the photoallerated product is one of the effective methods for directly constructing carbon-carbon bonds. In 2017, Melchiorre and colleagues reported a chiral amine catalyzed intermolecular asymmetric Michael-type capture process of a photo-enolated product (as shown in FIG. 2). Based on the high activity and nucleophilic characteristics of the photoenolization intermediate hydroxyphthalic carbon quinone, many complex organic compounds have been synthesized that are not otherwise readily available, in combination with a number of electrophiles.
Therefore, it is assumed that the strong nucleophilicity of the photoallerylated intermediate reacts with electrophilic isatin C3 (carbonyl group at position 3), and the green and efficient synthesis of 3-alkyl-3-hydroxyindol-2-one and its derivatives can be realized.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a method for preparing 3-alkyl-3-hydroxyindol-2-one and its derivatives; the second object of the present invention is to provide 3-alkyl-3-hydroxyindol-2-ones and derivatives thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
a process for the preparation of 3-alkyl-3-hydroxyindol-2-ones and derivatives thereof, said process having the reaction formula:
wherein R is1Is hydrogen, halogen, alkyl, alkoxy, R2Is hydrogen, alkyl, allyl, benzyl, R3Is hydrogen, halogen, alkyl, R4Is hydrogen, halogen or trifluoromethoxy.
Preferably, said R is1Is H, F, Cl, Br, I, methyl, methoxy, R2Is hydrogen, alkyl, allyl, benzyl, R3Is hydrogen, halogen, alkyl, R4Is hydrogen, halogen or trifluoromethoxy.
Preferably, the preparation method specifically comprises the following steps: dissolving the compound III and the compound II in an organic solvent, reacting at room temperature under the irradiation of an ultraviolet lamp, removing the organic solvent, and purifying by chromatography to obtain the compound I, namely the product 3-alkyl-3-hydroxyindole-2-ketone and the derivative thereof.
More preferably, the molar ratio of the compound III to the compound II is 3: 1-9.
Further preferably, the organic solvent is any one or more of acetonitrile, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, xylene or toluene.
Further preferably, the power of the ultraviolet lamp irradiation adopted during the ultraviolet lamp irradiation is 9-20W; the irradiation time of the ultraviolet lamp is 12-48 h.
Preferably, a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1-5: 1 is used as an eluent during the chromatographic purification.
2. The product was prepared according to the above preparation method.
Preferably, the structural formula of the product is shown as the following I-1-I-30:
the invention has the beneficial effects that:
the invention relates to a preparation method of 3-alkyl-3-hydroxyindole-2-ketone and derivatives thereof, which realizes the high-efficiency synthesis of the 3-alkyl-3-hydroxyindole-2-ketone and the derivatives thereof, does not need any catalyst or additive, and in the reaction, a substrate compound II undergoes an enol interconversion process under the irradiation of ultraviolet light to generate a hydroxyphthaline intermediate which is then captured by cheap and easily obtained isatin to obtain a corresponding target product. The reaction of the preparation method has good functional group tolerance and wide substrate range, can synthesize various 3-alkyl-3-hydroxyindole-2-ketone compounds and derivatives thereof, has high yield, and shows huge synthesis potential in organic synthesis.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The objectives and other advantages of the invention may be realized and attained by the means of the instrumentalities and combinations particularly pointed out hereinafter.
Drawings
For the purposes of promoting a better understanding of the objects, aspects and advantages of the invention, reference will now be made to the following detailed description taken in conjunction with the accompanying drawings in which:
FIG. 1 is a dipeptide catalyzed aldol condensation reaction of acetone and N-alkyl isatin, wherein in A dipeptide is used as a catalyst, in B quinidine thiourea is used as a catalyst, and in C metal is used as a catalyst;
FIG. 2 is a chiral amine catalyzed intermolecular asymmetric Michael-type trapping of a photo-enolate product;
FIG. 3 shows an emission spectrum (A) of an optimal light source and an ultraviolet-visible absorption spectrum (B) of a reactant;
FIG. 4 shows the photoanalysis deuteration reaction of ortho-benzyl position of compound II-30 (2-methylbenzophenone);
FIG. 5 is the NMR spectrum of the deuterated product (1H NMR)；
Fig. 6 is a High Resolution Mass Spectrometry (HRMS) spectrum of a deuterated product;
fig. 7 is a mechanism analysis diagram.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention. It should be noted that the drawings provided in the following embodiments are only for illustrating the basic idea of the present invention in a schematic way, and the features in the following embodiments and examples may be combined with each other without conflict.
Example 1
Dissolving 0.2mmol of compound III-1 (5-fluoroindoline-2, 3-dione) and 0.3mmol of compound II-2 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 1:1 as eluent, Rfvalue 0.2) to obtain 65.0mg of a white solid compound I-1(3- (2-benzoylbenzyl) -5-fluoro-3-hydroxyindolin-2-one) (Mp 181.5 to 183.7 ℃), yield 90%, structural formula:
1H NMR(600MHz,CDCl3):δ8.60(s,1H),7.76(d,J＝7.6Hz,2H),7.61(t,J＝7.4Hz,1H),7.50(t,J＝7.3Hz,1H),7.45(t,J＝8.0Hz,3H),7.37(t,J＝7.4Hz,1H),7.21(d,J＝7.6Hz,1H),6.88(t,J＝9.2Hz,1H),6.80(dd,J＝7.7,3.5Hz,1H),6.67(dd,J＝7.8,2.1Hz,1H),3.59(d,J＝14.0Hz,1H),3.01(d,J＝14.0Hz,1H)。
13C NMR(151MHz,CDCl3):δ199.4,181.0,159.7(C-F,1JC-F＝241.6Hz),158.1(C-F,1JC-F＝241.6Hz),138.7,137.7,136.3,134.5,133.8(C-F,3JC-F＝15.1Hz),133.7(C-F,3JC-F＝15.1Hz),132.6,132.5,131.2,131.1,131.0,128.5,126.7,115.9(C-F,2JC-F＝30.2Hz),115.7(C-F,2JC-F＝30.2Hz),113.9(C-F,2JC-F＝30.2Hz),113.7(C-F,2JC-F＝30.2Hz),111.1(C-F,3JC-F＝15.1Hz),111.0(C-F,3JC-F＝15.1Hz),77.1,40.8。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H16FNO3 362.1187；found:362.1186；19F NMR(565MHz,CDCl3):δ-121.8。
example 2
Dissolving 0.2mmol of compound III-2 (5-chloroindoline-2, 3-dione) and 0.3mmol of compound II-2 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 61.2mg of a white solid compound I-2(3- (2-benzoylbenzyl) -5-chloro-3-hydroxyindolin-2-one) (Mp is 182.8 to 184.9 ℃), yield 81%, structural formula:
1H NMR(600MHz,DMSO-d6):δ10.26(s,1H),7.67-7.60(m,1H),7.52-7.41(m,5H),7.36(d,J＝7.4Hz,1H),7.32(t,J＝7.0Hz,1H),7.17(d,J＝7.2Hz,1H),7.03(d,J＝7.6Hz,1H),6.64(d,J＝8.1Hz,1H),6.58(s,1H),6.21(s,1H),3.66(d,J＝13.4Hz,1H),3.10(d,J＝13.4Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ197.5,179.1,140.8,139.6,137.8,135.0,133.5,133.2,133.1,130.5,130.3,129.7,129.3,128.8,126.7,126.2,125.4,111.3,77.1,39.2。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H16ClNO3 378.0891；found:378.0891。
example 3
Dissolving 0.2mmol of compound III-3 (5-bromoindoline-2, 3-dione) and 0.3mmol of compound II-3 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 57.4mg of a white solid compound I-3(3- (2-benzoylbenzyl) -5-bromo-3-hydroxyindolin-2-one) (Mp 190.6 to 193.2 ℃), yield 68%, structural formula:
1H NMR(600MHz,DMSO-d6):δ10.26(s,1H),7.66-7.60(m,1H),7.52-7.40(m,5H),7.35(d,J＝7.2Hz,1H),7.31(t,J＝6.8Hz,1H),7.17(d,J＝7.7Hz,2H),6.68(s,1H),6.59(d,J＝8.1Hz,1H),6.20(s,1H),3.64(d,J＝13.4Hz,1H),3.08(d,J＝13.4Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ197.4,178.9,141.1,139.5,137.7,134.9,133.5,133.4,133.0,132.0,130.4,130.2,129.6,128.7,128.0,126.6,113.8,111.8,76.9,39.1。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H16BrNO3 422.0386；found:422.0385。
example 4
Dissolving 0.2mmol of compound III-4 (5-iodoindoline-2, 3-dione) and 0.3mmol of compound II-4 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 86.3mg of white solid compound I-4(3- (2-benzoylbenzyl) -3-hydroxy-5-iodoindolin-2-one) (Mp 199.8-203.0 ℃), yield 92%, structural formula:
1H NMR(600MHz,DMSO-d6):δ10.23(s,1H),7.64-7.62(m,1H),7.48-7.42(m,5H),7.34-7.30(m,3H),7.15(d,J＝7.6Hz,1H),6.81(s,1H),6.47(d,J＝8.1Hz,1H),6.16(s,1H),3.61(d,J＝13.4Hz,1H),3.03(d,J＝13.4Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ197.4,178.7,141.6,139.6,137.8,137.8,135.0,133.9,133.6,133.4,133.0,130.3,130.3,129.7,128.7,126.5,112.3,84.9,76.8,39.1。
example 5
Dissolving 0.2mmol of compound III-5 (5-methyl indoline-2, 3-dione) and 0.3mmol of compound II-5 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) gave 63.6mg of a white solid compound I-5(3- (2-benzoylbenzyl) -3-hydroxy-5-methylindolin-2-one) (Mp 189.7 to 193.8 ℃), yield 89%, structural formula:
1H NMR(600MHz,CDCl3):δ8.05(s,1H),7.68(d,J＝7.4Hz,2H),7.58(t,J＝7.4Hz,1H),7.43(m,3H),7.38(d,J＝7.1Hz,1H),7.32(t,J＝7.3Hz,1H),7.25(s,1H),6.94(d,J＝7.7Hz,1H),6.78(s,1H),6.70(d,J＝7.9Hz,1H),3.71(d,J＝13.8Hz,1H),3.07(d,J＝13.8Hz,1H),2.10(s,3H)。
13C NMR(151MHz,CDCl3):δ199.0,180.5,138.6,137.8,137.7,134.8,133.7,133.3,132.1,130.9,130.9,130.6,130.5,129.6,128.2,126.5,126.3,109.8,77.0,40.6,20.9。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C23H19NO3 358.1438；found:358.1436。
example 6
Dissolving 0.2mmol of compound III-6 (5-methoxyindoline-2, 3-dione) and 0.3mmol of compound II-6 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 67.2mg of a white solid compound I-6(3- (2-benzoylbenzyl) -3-hydroxy-5-methoxyindolin-2-one) (Mp 174.5 to 176.2 ℃), yield 90%, structural formula:
1H NMR(600MHz,DMSO-d6):δ9.91(s,1H),7.60(t,J＝6.6Hz,1H),7.46-7.39(m,5H),7.34(d,J＝7.6Hz,1H),7.26(t,J＝7.4Hz,1H),7.11(d,J＝7.6Hz,1H),6.51(s,2H),6.21(s,1H),6.03(s,1H),3.65(d,J＝13.3Hz,1H),3.37(s,3H),3.04(d,J＝13.3Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ197.5,179.3,154.9,139.6,137.8,135.3,134.9,133.2,132.9,132.2,130.3,130.3,129.6,128.6,126.3,114.1,111.9,110.2,77.3,55.3,39.3；HRMS(ESI-TOF)m/z:[M+H]+calcd for C23H19NO4 374.1387；found:374.1385。
example 7
Dissolving 0.2mmol of compound III-7 (6-bromoindoline-2, 3-dione) and 0.3mmol of compound II-7 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 76.9mg of a white solid compound I-7(3- (2-benzoylbenzyl) -6-bromo-3-hydroxyindolin-2-one) (Mp 216.1 to 219.5 ℃), yield 91%, structural formula:
1H NMR(600MHz,DMSO-d6):δ10.26(s,1H),7.68-7.62(m,1H),7.47(d,J＝3.8Hz,4H),7.43(t,J＝7.3Hz,1H),7.33-7.30(m,2H),7.17(d,J＝7.3Hz,1H),6.76(s,1H),6.69(d,J＝7.7Hz,1H),6.55(d,J＝7.7Hz,1H),6.14(s,1H),3.64(d,J＝13.3Hz,1H),3.06(d,J＝13.3Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ197.4,179.3,143.7,139.6,137.7,134.9,133.4,133.2,130.5,130.4,129.6,128.8,127.0,126.6,124.5,122.2,112.7,76.8,39.2。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H16BrNO3 422.0386；found:422.0385。
example 8
Dissolving 0.2mmol of compound III-8 (6-methoxyindoline-2, 3-dione) and 0.3mmol of compound II-8 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 5:1 as eluent, Rfvalue ═ 0.2) gave compound I-8(3- (2-benzoylbenzyl) -3-hydroxy-6-methoxyindolin-2-one) as a white solid (Mp 182.3-184.6 ℃)59.7mg, the yield is 80 percent, and the structural formula is as follows:
1H NMR(600MHz,DMSO-d6):δ10.04(s,1H),7.66-7.59(m,1H),7.52-7.43(m,4H),7.41(t,J＝7.4Hz,1H),7.33(d,J＝7.5Hz,1H),7.28(t,J＝7.3Hz,1H),7.14(d,J＝7.4Hz,1H),6.54(d,J＝8.2Hz,1H),6.16(d,J＝1.9Hz,1H),6.05(dd,J＝8.1,1.9Hz,1H),5.92(s,1H),3.62(d,J＝13.6Hz,1H),3.60(s,3H),3.05(d,J＝13.3Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ197.3,179.7,160.4,143.1,139.6,137.6,135.3,133.1,132.9,130.3,130.2,129.3,128.4,126.2,125.9,122.8,106.1,96.7,76.5,55.3,39.2。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C23H19NO4 374.1387；found:374.1384。
example 9
Dissolving 0.2mmol of compound III-9 (4-bromoindoline-2, 3-dione) and 0.3mmol of compound II-9 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue ═ 0.2) to give 78.5mg of a white solid compound I-9(3- (2-benzoylbenzyl) -4-bromo-3-hydroxyindolin-2-one) (Mp 202.3 to 204.8 ℃) in a yield of 93%, and having a structural formula:
1H NMR(600MHz,DMSO-d6):δ10.20(s,1H),7.63(t,J＝7.3Hz,1H),7.56-7.51(m,2H),7.49-7.43(m,2H),7.26(t,J＝7.5Hz,1H),7.21(t,J＝7.4Hz,1H),7.09(d,J＝7.6Hz,1H),7.06(d,J＝7.7Hz,1H),6.95(t,J＝7.9Hz,1H),6.82(d,J＝8.1Hz,1H),6.57(d,J＝7.7Hz,1H),6.12(s,1H),3.73(d,J＝13.2Hz,1H),3.42(d,J＝13.2Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ196.7,178.2,144.3,139.7,137.7,134.4,133.3,132.0,131.4,130.4,130.1,129.4,128.9,128.6,126.4,126.0,119.7,109.1,78.7,37.0。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H16BrNO3 422.0386；found:422.0384。
example 10
Dissolving 0.2mmol of compound III-10 (7-methyl indoline-2, 3-dione) and 0.3mmol of compound II-10 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 70.8mg of a white solid compound I-10(3- (2-benzoylbenzyl) -3-hydroxy-7-methylindolin-2-one) (Mp 180.9 to 183.1 ℃), yield 99%, structural formula:
1H NMR(600MHz,DMSO-d6):δ10.15(s,1H),7.61(t,J＝7.1Hz,1H),7.51(d,J＝7.4Hz,2H),7.45(t,J＝7.5Hz,2H),7.39(t,J＝7.3Hz,1H),7.33-7.24(m,2H),7.15(d,J＝7.4Hz,1H),6.82(d,J＝7.5Hz,1H),6.53(t,J＝7.4Hz,1H),6.48(d,J＝7.1Hz,1H),5.94(s,1H),3.57(d,J＝13.5Hz,1H),3.05(d,J＝13.5Hz,1H),2.07(s,3H)。
13C NMR(600MHz,DMSO-d6):δ197.6,179.9,140.4,139.9,138.0,135.4,133.3,133.0,131.1,130.6,130.5,130.2,129.4,128.6,126.4,122.5,121.7,119.0,76.9,39.5,16.7。
example 11
0.2mmol of the compound III-11 (4-bromo-5-methylindoline-2, 3-dione) and 0.3mmol of the compound II-11 (phenyl (o-tolyl) methanone) were dissolved in 2ml of an organic solvent (toluene), irradiated with an ultraviolet lamp of power 15W, and reacted at room temperature for 3 hoursRemoving organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue ═ 0.2) to give 52.4mg of a white solid compound I-11(3- (2-benzoylbenzyl) -4-bromo-3-hydroxy-5-methylindolin-2-one) in a yield of 60%, the structural formula being:
1H NMR(600MHz,DMSO-d6):δ10.11(s,1H),7.64(t,J＝7.1Hz,1H),7.46-7.41(m,4H),7.35-7.30(m,1H),7.21(t,J＝7.2Hz,2H),7.05(d,J＝7.1Hz,1H),6.93(d,J＝7.8Hz,1H),6.48(d,J＝7.7Hz,1H),6.07(s,1H),4.01(d,J＝13.1Hz,1H),3.30(d,J＝13.1Hz,1H),1.86(s,3H)。
13C NMR(151MHz,DMSO-d6):δ196.4,178.5,141.9,139.7,137.3,134.5,133.3,132.4,131.5,131.1,130.4,130.2,129.2,129.1,128.5,126.3,122.4,108.9,79.5,36.8,21.9。
example 12
Dissolving 0.2mmol of compound III-12 (4, 7-dichloroindoline-2, 3-dione) and 0.3mmol of compound II-12 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 49.5mg of a white solid compound I-12(3- (2-benzoylbenzyl) -4, 7-dichoro-3-hydroxyindolin-2-one) (Mp 183.3 to 185.6 ℃), yield 60%, structural formula:
1H NMR(600MHz,DMSO-d6):δ10.68(s,1H),7.64(t,J＝6.8Hz,1H),7.55-7.45(m,4H),7.35(t,J＝7.3Hz,1H),7.27(t,J＝7.3Hz,1H),7.16(d,J＝7.5Hz,1H),7.14(d,J＝7.5Hz,1H),7.02(d,J＝8.6Hz,1H),6.60(d,J＝8.6Hz,1H),6.31(s,1H),3.81(d,J＝13.3Hz,1H),3.39(d,J＝13.3Hz,1H),3.38(s,1H)。
13C NMR(151MHz,DMSO-d6):δ196.6,178.4,141.6,139.6,137.5,134.1,133.6,132.6,131.1,130.5,130.5,129.9,129.6,128.9,128.8,126.8,124.3,113.1,79.1,37.4。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H15Cl2NO3 412.0502；found:412.0499。
example 13
Dissolving 0.2mmol of compound III-13 (5, 7-dimethylindoline-2, 3-dione) and 0.3mmol of compound II-13 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to give 48.3mg of a white solid compound I-13(3- (2-benzoylbenzyl) -3-hydroxy-5, 7-dimethyllidin-2-one) (Mp 191.6 to 193.3 ℃), yield 65%, structural formula:
1H NMR(600MHz,DMSO-d6):δ10.05(s,1H),7.62(t,J＝7.0Hz,1H),7.44(t,J＝7.5Hz,2H),7.40(m,3H),7.35(d,J＝7.6Hz,1H),7.26(t,J＝7.3Hz,1H),7.10(d,J＝7.5Hz,1H),6.55(s,1H),6.31(s,1H),5.94(s,1H),3.72(d,J＝13.1Hz,1H),3.08(d,J＝13.1Hz,1H),2.01(s,3H),1.77(s,3H)。
13C NMR(151MHz,DMSO-d6):δ197.5,179.8,139.5,138.0,137.9,135.5,133.3,133.2,131.0,130.8,130.7,130.4,129.7,128.6,126.3,123.3,118.6,77.4,39.3,20.8,16.6。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C24H21NO3 372.1594；found:372.1593。
example 14
0.2mmol of the compound III-14 (1-allylindoline-2, 3-di-n-butyl ether)Ketone) and 0.3mmol of the compound II-14 (phenyl (o-tolyl) methanone) were dissolved in 2ml of an organic solvent (toluene), irradiated with an ultraviolet lamp of power 15W, reacted at room temperature for 36 hours, the organic solvent was removed, and purified by chromatography (using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 as an eluent, Rfvalue 0.2) to obtain 61.4mg of a white solid compound I-14(1-allyl-3- (2-benzoylbenzyl) -3-hydroxyindolin-2-one) (Mp 137.2 to 138.4 ℃), yield 80%, structural formula:
1H NMR(600MHz,DMSO-d6):δ7.63(t,J＝6.9Hz,1H),7.48-7.44(m,4H),7.37(t,J＝7.5Hz,1H),7.28(t,J＝7.4Hz,1H),7.24(d,J＝7.7Hz,1H),7.15(d,J＝7.5Hz,1H),7.07(t,J＝7.6Hz,1H),6.82(d,J＝7.2Hz,1H),6.71(d,J＝7.8Hz,1H),6.68(t,J＝7.4Hz,1H),6.19(s,1H),5.61(ddd,J＝15.2,9.9,4.7Hz,1H),5.00(d,J＝10.4Hz,1H),4.74(d,J＝17.2Hz,1H),4.23(dd,J＝16.8,2.4Hz,1H),4.01(dd,J＝16.8,4.6Hz,1H),3.66(d,J＝13.3Hz,1H),3.21(d,J＝13.3Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ197.4,177.3,142.6,139.7,137.8,135.0,133.4,133.0,132.1,130.6,130.5,130.4,129.6,129.5,128.7,126.5,124.9,122.5,116.9,109.3,76.8,41.7,39.6。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C25H21NO3 384.1594；found:384.1594。
example 15
Dissolving 0.2mmol of compound III-15 (1- (cyclopropylmethyl) indoline-2, 3-dione) and 0.3mmol of compound II-15 (phenyl (o-tolyl) methanone) in 2ml of organic solvent (toluene), irradiating with an ultraviolet lamp with power of 15W, reacting at room temperature for 36h, removing the organic solvent, and purifying by chromatography (using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 as an eluent, Rfvalue is 0.2) to obtain white solid compound I-15(3- (2-benzoylbenzyl) -1- (cyclopropolymethyl) -3-hydroxyindolin-2-one) (Mp is160.1-162.3 ℃)62.0mg, the yield is 78%, and the structural formula is as follows:
1H NMR(600MHz,DMSO-d6):δ7.63-7.59(m,1H),7.52-7.43(m,4H),7.38(t,J＝7.4Hz,1H),7.29(d,J＝7.7Hz,1H),7.26(t,J＝7.5Hz,1H),7.13(d,J＝7.4Hz,1H),7.07(t,J＝7.6Hz,1H),6.88(d,J＝7.7Hz,1H),6.77(d,J＝7.1Hz,1H),6.64(t,J＝7.4Hz,1H),6.13(s,1H),3.66(d,J＝13.4Hz,1H),3.45(dd,J＝14.4,6.9Hz,1H),3.33(dd,J＝14.8,7.0Hz,1H),3.12(d,J＝13.4Hz,1H),0.97-0.84(m,1H),0.39-0.30(m,2H),0.21(dd,J＝31.3,9.8Hz,2H)。
13C NMR(151MHz,DMSO-d6):δ197.4,177.6,143.0,139.6,137.8,135.0,133.4,132.8,130.6,130.5,130.4,129.5,129.5,128.7,126.4,124.9,122.3,109.0,76.6,43.6,39.7,9.8,4.0,3.9。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C26H23NO3 398.1751；found:398.1750。
example 16
Dissolving 0.2mmol of compound III-16 (1-benzyl indoline-2, 3-dione) and 0.3mmol of compound II-16 (phenyl (o-tolyl) ketone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 78.9mg of a white solid compound I-16(3- (2-benzoylbenzyl) -1-benzyl-3-hydroxyindolin-2-one) (Mp 136.5 to 137.7 ℃), yield 91%, structural formula:
1H NMR(600MHz,CDCl3):δ7.64(d,J＝7.0Hz,2H),7.55(t,J＝6.6Hz,1H),7.45(d,J＝6.8Hz,1H),7.38-7.32(m,4H),7.30-7.23(m,5H),7.12(d,J＝6.1Hz,1H),7.08-7.02(m,2H),6.80(t,J＝7.0Hz,1H),6.60(d,J＝7.4Hz,1H),5.41(s,1H),5.05(d,J＝15.4Hz,1H),4.63(d,J＝15.4Hz,1H),3.83(d,J＝13.5Hz,1H),3.11(d,J＝13.5Hz,1H)。
13C NMR(151MHz,CDCl3):δ198.8,178.4,142.5,138.9,137.7,135.8,134.8,133.9,133.3,131.0,130.8,130.7,130.0,129.4,128.9,128.3,127.6,127.3,126.4,125.5,122.6,109.3,76.7,43.9,40.9。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C29H23NO3 434.1751；found:434.1748。
example 17
Dissolving 0.2mmol of compound III-17 (indoline-2, 3-dione) and 0.3mmol of compound II-17 ((4-fluorophenyl) (o-tolyl) methanone) in 2ml of organic solvent (toluene), irradiating with an ultraviolet lamp with power of 15W, reacting at room temperature for 36h, removing the organic solvent, and purifying by chromatography (using a mixed solvent of petroleum ether and ethyl acetate at a volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 64.3mg of a white solid compound I-17(3- (2- (4-fluorobenzoyl) benzyl) -3-hydroxyindolin-2-one) (Mp is 146.1-147.3 ℃), yield is 89%, and structural formula is:
1H NMR(600MHz,DMSO-d6):δ10.11(s,1H),7.62-7.51(m,2H),7.39(t,J＝7.5Hz,1H),7.33-7.23(m,4H),7.16(d,J＝7.1Hz,1H),7.02(t,J＝7.6Hz,1H),6.72-6.55(m,3H),6.04(s,1H),3.60(d,J＝13.4Hz,1H),3.09(d,J＝13.4Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ196.1,179.5,166.2(C-F,1JC-F＝256.7Hz),164.5(C-F,1JC-F＝256.7Hz),142.0,139.6,135.3,134.6,133.5(C-F,3JC-F＝15.1Hz),133.4(C-F,3JC-F＝15.1Hz),133.2,131.3,130.4,129.5,129.4,126.5,125.2,121.8,115.9(C-F,2JC-F＝30.2Hz),115.7(C-F,2JC-F＝30.2Hz),109.9,76.9,39.5。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H16FNO3 362.1187；found:362.1185。
example 18
Dissolving 0.2mmol of compound III-18 (indoline-2, 3-dione) and 0.3mmol of compound II-18 (4-bromophenyl) (o-tolyl) methanone in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 65.9mg of a white solid compound I-18(3- (2- (4-bromobenzoyl) benzyl) -3-hydroxyindolin-2-one) (Mp is 171.8 to 173.5 ℃), yield 78%, structural formula:
1H NMR(600MHz,DMSO-d6):δ10.10(s,1H),7.71-7.65(m,2H),7.46-7.42(m,2H),7.39(t,J＝7.5Hz,1H),7.30(t,J＝7.5Hz,1H),7.26(d,J＝7.7Hz,1H),7.17(d,J＝7.6Hz,1H),7.03(t,J＝7.4Hz,1H),6.69-6.59(m,3H),6.01(s,1H),3.58(d,J＝13.3Hz,1H),3.08(d,J＝13.3Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ196.6,179.4,142.0,139.4,137.0,135.3,133.3,132.5,131.9,131.3,130.5,129.5,127.5,126.6,125.2,121.8,110.0,76.9,39.4。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H16BrNO3 422.0386；found:422.0385。
example 19
Dissolving 0.2mmol of compound III-19 (indoline-2, 3-dione) and 0.3mmol of compound II-19 (o-tolyl (4- (trifluoromethoxy) phenyl) methanone) in 2ml of organic solvent (toluene), irradiating with an ultraviolet lamp with power of 15W, reacting at room temperature for 36h, removing the organic solvent, and purifying by chromatography (using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 as a washing solvent)Dealcoholizing agent, Rfvalue 0.2) to obtain white solid compound I-19(3-hydroxy-3- (2- (4- (trifluoromethyl) benzoyl) benzyl) indolin-2-one) (Mp is 160.1-162.9 ℃)70.0mg, the yield is 82%, and the structural formula is:
1H NMR(600MHz,DMSO-d6):δ10.09(s,1H),7.61(d,J＝8.6Hz,2H),7.43(d,J＝8.2Hz,2H),7.39(t,J＝7.5Hz,1H),7.29(t,J＝7.2Hz,1H),7.25(d,J＝7.7Hz,1H),7.17(d,J＝7.5Hz,1H),6.97(t,J＝7.4Hz,1H),6.65-6.59(m,2H),6.55(t,J＝7.3Hz,1H),6.01(s,1H),3.60(d,J＝13.3Hz,1H),3.06(d,J＝13.3Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ196.0,179.4,151.8,142.0,139.3,136.8,135.3,133.4,132.9,131.3,130.5,129.5,129.4,126.6,125.2,123.1(C-F,1JC-F＝256.7Hz),121.7,121.4(C-F,1JC-F＝256.7Hz),120.9,119.7(C-F,1JC-F＝256.7Hz),118.0(C-F,1JC-F＝256.7Hz),109.9,76.9,39.4。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C23H16F3NO4 428.1104；found:428.1104；19F NMR(565MHz,DMSO-d6):δ-56.5。
example 20
Dissolving 0.2mmol of compound III-20 (indoline-2, 3-dione) and 0.3mmol of compound II-20 ((3-chlorophenyl) (o-tolyl) methanone) in 2ml of organic solvent (toluene), irradiating with an ultraviolet lamp with power of 15W, reacting at room temperature for 36h, removing the organic solvent, and purifying by chromatography (using a mixed solvent of petroleum ether and ethyl acetate at a volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 55.2mg of a white solid compound I-20(3- (2- (3-chlorobenzoyl) benzyl) -3-hydroxyindolin-2-one) (Mp 117.5 to 119.3 ℃), yield 73%, structural formula:
1H NMR(600MHz,DMSO-d6):δ10.10(s,1H),7.70(d,J＝7.1Hz,1H),7.54-7.45(m,2H),7.42(t,J＝6.9Hz,1H),7.34-7.25(m,3H),7.17(d,J＝7.1Hz,1H),7.00(t,J＝7.1Hz,1H),6.65(t,J＝8.4Hz,2H),6.56(t,J＝7.2Hz,1H),6.04(s,1H),3.66(d,J＝13.2Hz,1H),3.09(d,J＝13.2Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ196.1,179.4,142.1,139.9,139.0,135.5,133.6,133.4,133.1,131.3,130.8,130.8,130.1,129.6,129.5,129.1,126.6,125.2,121.8,109.9,77.0,39.4。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H16ClNO3 378.0819；found:378.0889。
example 21
Dissolving 0.2mmol of compound III-21 (indoline-2, 3-dione) and 0.3mmol of compound II-21 ((3-bromophenyl) (o-tolyl) methanone) in 2ml of organic solvent (toluene), irradiating with an ultraviolet lamp with power of 15W, reacting at room temperature for 36h, removing the organic solvent, and purifying by chromatography (using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 as an eluent, Rfvalue 0.2) to obtain 56.6mg of a white solid compound I-21(3- (2- (3-bromobenzoyl) benzyl) -3-hydroxyindolin-2-one) (Mp 142.8 to 145.9 ℃) in a yield of 67%, which had the following structural formula:
1H NMR(600MHz,DMSO-d6):δ10.10(s,1H),7.82(d,J＝7.8Hz,1H),7.52(d,J＝7.7Hz,1H),7.48-7.39(m,3H),7.33-7.28(m,2H),7.17(d,J＝7.5Hz,1H),7.00(t,J＝7.6Hz,1H),6.65(t,J＝7.7Hz,2H),6.56(t,J＝7.4Hz,1H),6.04(s,1H),3.66(d,J＝13.3Hz,1H),3.10(d,J＝13.3Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ196.0,179.4,142.0,140.1,138.9,136.0,135.5,133.4,133.0,131.2,131.0,130.8,129.6,129.5,129.4,126.6,125.2,122.0,121.8,109.9,77.0,39.3。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H16BrNO3 422.0386；found:422.0384。
example 22
Dissolving 0.2mmol of compound III-22 (indoline-2, 3-dione) and 0.3mmol of compound II-22 ((3-fluoro-2-methylphenyl) (phenyl) methanone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 60.78mg of white solid compound I-22(3- (2-benzoyl-6-fluorobenzyl) -3-hydroxyindolin-2-one) (Mp is 159.3-161.2 ℃), yield is 84%, and structural formula is:
1H NMR(600MHz,DMSO-d6):δ10.20(s,1H),7.78(d,J＝7.6Hz,2H),7.65(t,J＝7.3Hz,1H),7.53(t,J＝7.6Hz,2H),7.42-7.37(m,1H),7.27(t,J＝8.9Hz,1H),7.15-7.08(m,2H),6.81-6.74(m,2H),6.57(d,J＝7.3Hz,1H),5.82(s,1H),3.43(d,J＝13.6Hz,1H),3.11(d,J＝13.6Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ197.1,179.7,162.7(C-F,1JC-F＝241.6Hz),161.1(C-F,1JC-F＝241.6Hz),142.5(C-F,3JC-F＝15.1Hz),142.4(C-F,3JC-F＝15.1Hz),141.2,137.7,133.7,131.5,130.7,129.7,128.8,128.6,128.6,125.6,125.6,124.6,122.5(C-F,3JC-F＝15.1Hz),122.4(C-F,3JC-F＝15.1Hz),122.2,117.8(C-F,2JC-F＝30.2Hz),117.6(C-F,2JC-F＝30.2Hz),110.3,76.1,32.0。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H16FNO3 362.1187；found:362.1185；19F NMR(565MHz,DMSO-d6):δ-112.9。
example 23
Dissolving 0.2mmol of compound III-23 (indoline-2, 3-dione) and 0.3mmol of compound II-23 ((2, 4-dimethylphenyl) (phenyl) methanone) in 2ml of organic solvent (toluene), irradiating with an ultraviolet lamp with power of 15W, reacting at room temperature for 36h, removing the organic solvent, and purifying by chromatography (using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 as an eluent, Rfvalue 0.2) to obtain 65.8mg of a white solid compound I-23(3- (2-benzoyl-5-methyllbenzyl) -3-hydroxyindolin-2-one) (Mp: 148.7-151.1), yield 92%, structural formula:
1H NMR(600MHz,CDCl3):δ8.38(s,1H),7.76(d,J＝7.6Hz,2H),7.58(t,J＝7.4Hz,1H),7.44(t,J＝7.6Hz,2H),7.34(d,J＝7.8Hz,1H),7.20(t,J＝7.4Hz,1H),7.15(d,J＝7.8Hz,1H),6.98(s,1H),6.95(d,J＝7.1Hz,1H),6.92(t,J＝7.4Hz,1H),6.87(d,J＝7.8Hz,1H),6.35(s,1H),3.61(d,J＝13.9Hz,1H),2.97(d,J＝13.9Hz,1H),2.37(s,3H)。
13C NMR(151MHz,CDCl3):δ199.3,180.9,141.3,140.3,138.1,135.8,135.0,134.7,133.3,131.6,131.0,131.0,129.3,128.2,127.0,125.8,122.1,110.2,76.8,40.8,21.4。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C23H19NO3 358.1438；found:358.1436。
example 24
Dissolving 0.2mmol of compound III-24 (indoline-2, 3-dione) and 0.3mmol of compound II-24 ((4-chloro-2-methylphenyl) (phenyl) methanone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue ═ 0.2) to give a white solid compound I-24(3- (2-benzoyl-5-chlorobenzoyl) -3-h60.2mg of ydorxindolin-2-one) (Mp is 165.7-167.2 ℃), yield is 82%, and structural formula is:
1H NMR(600MHz,DMSO-d6):δ10.18(s,1H),7.62(t,J＝7.3Hz,1H),7.52-7.44(m,4H),7.37(d,J＝8.2,1H),7.31(d,J＝2.3Hz,1H),7.19(d,J＝8.2Hz,1H),7.04(t,J＝7.4Hz,1H),6.72-6.63(m,3H),6.08(s,1H),3.49(d,J＝13.5Hz,1H),3.09(d,J＝13.5Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ196.6,179.2,141.9,138.6,138.0,137.8,134.9,133.6,132.8,131.4,131.2,130.5,129.6,128.9,126.6,125.1,122.0,110.1,76.6,39.2。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H16ClNO3 378.0891；found:378.0890。
example 25
Dissolving 0.2mmol of compound III-25 (indoline-2, 3-dione) and 0.3mmol of compound II-25 ((5-bromo-2-methylphenyl) (phenyl) methanone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 58.3mg of a white solid compound I-25(3- (2-benzoyl-4-bromobenzoyl) -3-hydroxyindolin-2-one) (Mp is 183.9 to 185.7 ℃), yield is 69%, and structural formula is:
1H NMR(600MHz,DMSO-d6):δ10.14(s,1H),7.66-7.59(m,2H),7.54-7.46(m,4H),7.30(d,J＝2.3Hz,1H),7.22(d,J＝8.4Hz,1H),7.07-7.02(m,1H),6.69-6.63(m,3H),6.05(s,1H),3.42(d,J＝13.6Hz,1H),3.00(d,J＝13.5Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ196.0,179.2,142.0,141.9,137.4,135.2,134.7,133.8,133.0,131.6,131.3,130.5,129.6,129.0,125.1,122.0,119.7,110.0,76.5,39.2。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C22H16BrNO3 422.0386；found:422.0384。
example 26
Dissolving 0.2mmol of compound III-26 (5-iodoindoline-2, 3-dione) and 0.3mmol of compound II-26 ((3-chlorophenyl) (o-tolyl) methanone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain 89.7mg of a white solid compound I-26(3- (2- (3-chlorobenzoyl) benzyl) -3-hydroxy-5-iodoindolin-2-one) (Mp is 195.0-197.2), yield is 89%, and structural formula is:
1H NMR(600MHz,DMSO-d6)：δ10.21(s,1H),7.69(d,J＝8.0Hz,1H),7.49(t,J＝7.9Hz,1H),7.44(t,J＝7.6Hz,1H),7.37(d,J＝7.8Hz,1H),7.35-7.25(m,3H),7.22(s,1H),7.14(d,J＝7.7Hz,1H),6.90(s,1H),6.47(d,J＝8.1Hz,1H),6.20(s,1H),3.78(d,J＝13.1Hz,1H),3.07(d,J＝13.1Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ196.2,178.7,141.9,139.8,138.7,138.0,135.2,133.9,133.8,133.7,133.6,133.3,131.0,130.9,130.0,129.8,129.1,126.8,112.3,85.2,77.3,39.1。
example 27
Dissolving 0.2mmol of compound III-27 (5-methoxyindoline-2, 3-dione) and 0.3mmol of compound II ((4-fluorophenyl) (o-tolyl) methanone) in 2ml of organic solvent (toluene), irradiating with an ultraviolet lamp with power of 15W, reacting at room temperature for 36h, removing the organic solvent, and purifying by chromatography (using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 2:1 as an eluent, Rfvalue 0.2) to obtain 50.9mg of compound I-27(3- (2- (4-fluorobenzoyl) benzyl) -3-hydroxy-5-methoxyindolin-2-one) (Mp 173.1-175.9 ℃) in 65% yield:
1H NMR(600MHz,DMSO-d6):δ9.94(s,1H),7.48(t,J＝6.3Hz,2H),7.42(t,J＝7.4Hz,1H),7.35(d,J＝7.6Hz,1H),7.31-7.24(m,3H),7.14(d,J＝7.4Hz,1H),6.53(t,J＝9.6Hz,2H),6.24(s,1H),6.06(s,1H),3.70(dd,J＝13.2Hz,1H),3.41(s,3H),3.07(dd,J＝13.2Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ196.1,179.3,166.3(C-F,1JC-F＝256.7Hz),164.6(C-F,1JC-F＝256.7Hz),155.0,139.4,135.3(C-F,2JC-F＝30.2Hz),135.1(C-F,2JC-F＝30.2Hz),134.6(C-F,3JC-F＝15.1Hz),134.5(C-F,3JC-F＝15.1Hz),133.3,133.2,132.3,130.6,129.6,126.5,115.8,115.7,114.1,112.1,110.3,77.5,55.4,39.4。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C23H18FNO4 392.1293；found:392.1291；19F NMR(565MHz,DMSO-d6):δ-106.5。
example 28
Dissolving 0.2mmol of compound III-28 (6-methoxyindoline-2, 3-dione) and 0.3mmol of compound II-28 ((3-bromophenyl) (o-tolyl) methanone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue ═ 0.2) to obtain 61.5mg of white solid product, i.e., compound I-28(3- (2- (3-bromobenzoyl) benzyl) -3-hydroxy-6-methoxyindolin-2-one), yield was 68%, formula:
1H NMR(600MHz,DMSO-d6):δ10.03(s,1H),7.80(d,J＝7.8Hz,1H),7.48-7.39(m,4H),7.32-7.27(m,2H),7.14(d,J＝7.6Hz,1H),6.53(d,J＝8.2Hz,1H),6.15(d,J＝2.3Hz,1H),6.01(d,J＝7.8Hz,1H),5.93(s,1H),3.69(d,J＝13.1Hz,1H),3.58(s,3H),3.05(d,J＝13.1Hz,1H)。
13C NMR(151MHz,DMSO-d6):δ195.9,179.8,160.7,143.4,139.9,138.8,136.0,135.7,133.6,132.9,130.9,130.8,129.6,129.4,126.5,126.2,122.8,122.0,106.3,96.9,76.8,55.6,39.3。
HRMS(ESI-TOF)m/z:[M+H]+calcd for C23H18BrNO4 452.0492；found:452.0490。
example 29
Dissolving 0.2mmol of compound III-29 (7-methyl indoline-2, 3-dione) and 0.3mmol of compound II-29 ((2, 4-dimethyl phenyl) (phenyl) methanone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 36h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue 0.2) to obtain a white solid product, namely compound I-29(3- (2-benzyl-5-methylbenzyl) -3-hydroxy-7-methylindolin-2-one) (Mp: 182.1-183.8 ℃)69.1mg, yield 68%, structural formula:
1H NMR(600MHz,DMSO-d6):δ10.15(s,1H),7.59(t,J＝7.2Hz,1H),7.50-7.40(m,4H),7.10-7.00(m,3H),6.80(d,J＝7.1Hz,1H),6.56-6.47(m,2H),5.94(s,1H),3.57(d,J＝13.3Hz,1H),3.05(d,J＝13.3Hz,1H),2.25(s,3H),2.06(s,3H)。
13C NMR(151MHz,DMSO-d6):δ197.7,180.0,140.5,140.0,138.4,137.1,135.6,133.9,133.2,131.2,130.6,130.5,129.9,128.6,126.9,122.6,121.7,119.0,77.1,39.5,21.6,16.8。
example 30
Dissolving 0.2mmol of compound III-30 (indoline-2, 3-dione) and 0.3mmol of compound II-30 (benzophenone) in 2ml of organic solvent (toluene), irradiating with 15W ultraviolet lamp, reacting at room temperature for 48h, removing organic solvent, and purifying by chromatography (using mixed solvent of petroleum ether and ethyl acetate at volume ratio of 2:1 as eluent, Rfvalue ═ 0.2) to obtain a white solid product, namely 66.6mg of compound I-30(3- (2-benzoylbenzyl) -3-hydroxyindolin-2-one), with a yield of 97%, and the structural formula:
1H NMR(400MHz,DMSO-d6):δ10.09(s,1H),7.61(t,J＝8.0Hz,1H),7.52-7.42(m,4H),7.37(d,J＝8.0Hz,1H),7.30-7.25(m,2H),7.14(d,J＝8.0Hz,1H),7.01(t,J＝4.0Hz,1H),6.67-6.56(m,3H),6.00(s,1H),3.56(d,J＝13.3Hz,1H),3.07(d,J＝13.3Hz,1H).
13C NMR(101MHz,DMSO-d6):δ197.4,179.3,141.8,139.7,137.9,135.2,133.2,132.8,131.2,130.4,130.1,129.4,129.3,128.6,126.3,125.1,121.7,109.7,76.7,39.3。
example 31
1. Effect of different organic solvents on the reaction
Compound I-30 was prepared by following the procedures for the preparation and starting materials in example 30, except that the organic solvent was replaced from toluene with acetonitrile, dichloromethane, dimethylsulfoxide, tetrahydrofuran and xylene, respectively. The yields of the products obtained with the different solvents are shown in table 1.
TABLE 1 yield of Compound I-30 prepared in different solvents
As can be seen from the influence of different organic solvents on the reaction in Table 1, the preparation method of the 3-alkyl-3-hydroxyindol-2-one (compound I-30) provided by the invention can obtain better yield in organic solvents such as toluene, acetonitrile, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, xylene and the like.
2. Effect of different reactant ratios on the reaction
Compound I-30 was prepared by following the procedures for the preparation and starting materials for the reaction in example 30, except that the molar ratios of compound III-30 and compound II-30 therein were changed from 0.2:0.3 to 0.2:0.2, 0.2:0.4, 0.2:0.6, 0.3:0.1, 0.2:0.1 and 0.15:0.1, respectively. The yields of the products obtained with different reactant ratios are shown in table 2.
TABLE 2 yield of Compound I-30 prepared at different reactant ratios
As can be seen from the influence of different reactant ratios on the reaction in Table 2, the molar ratio of the compound III-30 to the compound II-30 in the preparation method of the 3-alkyl-3-hydroxyindol-2-one (compound I-30) provided by the invention can be within the range of 3: 1-9, and higher yield can be obtained.
3. Effect of different reaction times on the reaction
Compounds I-30 were prepared by following the starting materials and preparation method of example 30, replacing only the reaction times from 48h with 12, 24 and 36h, respectively. The yields of the products obtained at different reaction times are shown in table 3.
TABLE 3 yield of Compound I-30 prepared at different reaction times
As can be seen from the influence of different reaction times on the reaction in Table 3, the reaction time in the preparation method of the 3-alkyl-3-hydroxyindol-2-one (compound I-30) provided by the invention can be within the range of 12-48 h, and a higher (more than 70%) yield is obtained.
4. Effect of different light conditions on the reaction
Compound I-30 was prepared by carrying out the reaction using the reaction starting materials and preparation method as in example 30, with only the light conditions being replaced from 15W UV lamp irradiation to 9W UV lamp irradiation, 20W UV lamp irradiation, 32W compact fluorescent lamp irradiation, 23W white light irradiation and dark conditions, respectively. The yields of the products obtained under different light conditions are shown in table 4.
TABLE 4 yield of Compound I-30 prepared under different light conditions
As can be seen from the influence of different illumination conditions on the reaction in Table 4, the illumination condition in the preparation method of the 3-alkyl-3-hydroxyindol-2-one (compound I-30) provided by the invention is ultraviolet lamp irradiation, the irradiation power can be carried out within the range of 9-20W, and a higher (greater than or equal to 85%) yield is obtained.
As can be seen from the reactions of examples 1 to 30, in the process for producing 3-alkyl-3-oxindole-2-ones and derivatives thereof according to the present invention, the reactants compound III and substituent R of compound II are used1Can be hydrogen, halogen, alkyl, alkoxy, R2Can be hydrogen, alkyl, allyl, benzyl, R3Can be hydrogen, halogen, alkyl, R4Can be hydrogen, halogen and alkyl, and can react with each other to prepare corresponding 3-alkyl-3-hydroxyindole-2-ketone and derivatives thereof; from example 31, it can be seen that the molar ratio of compound iii to compound ii can be in the range of 3: 1-9, the organic solvent can be any one or more of acetonitrile, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, xylene or toluene, and the compound iii and compound ii are irradiated by ultraviolet light during the reaction processThe power can be in the range of 9-20W; the irradiation time of the ultraviolet lamp can be within the range of 12-48 h, the formation of reaction products is not influenced, and higher yield is obtained.
Example 32
The mechanism of the preparation method of the 3-alkyl-3-hydroxyindole-2-ketone and the derivative thereof is explored:
to illustrate the reaction mechanism, a control experiment (see Table 4) was conducted to illustrate the reaction of example 30, and the reaction produced 97% of the target product I-30 under the irradiation of 15W ultraviolet light, while the reaction was monitored to produce a trace amount or no target product under the irradiation of white light or dark, indicating that the reaction occurring in the preparation method of the present invention may involve an energy transfer process.
By comparing the emission spectrum of the optimal light source (shown as A in FIG. 3) with the ultraviolet-visible absorption spectrum of the reactant (shown as B in FIG. 3), the absorption spectrum of the compound II-30 (2-methylbenzophenone) is found to be in the wavelength range of the emission spectrum of the light source, which indicates that the reactant compound II-30 (2-methylbenzophenone) can preferentially absorb light energy, generate an excited state and participate in subsequent reactions.
A deuteration experiment (as shown in FIG. 4) was then performed to explore the photochemical reactivity of the reactant compound II-30 (2-methylbenzophenone). Compound II-30 (2-methylbenzophenone) in a volume ratio of toluene to heavy water (D) of 2:12O) in a mixed solvent under a 15W ultraviolet lamp (lambda)max365nm), reaction for 24h, and then nuclear magnetic resonance hydrogen spectrum (c) (1H NMR) and High Resolution Mass Spectrometry (HRMS) a large substitution of the hydrogen atom at the ortho-methyl group in compound ii-30 (2-methylbenzophenone) with deuterium was observed (the hydrogen and carbon spectra are shown in fig. 5 and 6, respectively), indicating that compound ii-30 (2-methylbenzophenone) underwent a photoenolization process under uv irradiation.
According to the above experimental results and related reports, a possible reaction mechanism of the preparation method of the present invention is proposed, and the carbonyl group in the substrate compound II-30 (2-methylbenzophenone) absorbs light energy to generate singlet excited state S1B, decay to triplet state T by intersystem crossing (ISC) process1-B; after the triplet excited state undergoes a 1, 5-hydrogen atom transfer process, the generated diradical intermediate 2-I is rotated to generate a highly reactive enol intermediate 2-II, which is captured by isatin 2.1 to directly obtain a compound I-30, and the mechanism analysis is shown in FIG. 7.
Similarly, the same method is used to search the mechanism of other substrates (the structural formula is compound III and compound II), and the obtained result is the same, namely carbonyl in the substrate compound II absorbs light energy to generate singlet excited state S1B, decay to triplet state T by intersystem crossing (ISC) process1-B; after the triplet excited state undergoes a 1, 5-hydrogen atom transfer process, the generated diradical intermediate is rotated to produce a highly reactive enol intermediate, which is captured by isatin to directly yield 3-alkyl-3-hydroxyindol-2-one and its derivatives (compound I).
In conclusion, the preparation method of the 3-alkyl-3-hydroxyindole-2-ketone and the derivative thereof realizes the high-efficiency synthesis of the 3-alkyl-3-hydroxyindole-2-ketone and the derivative thereof, does not need any catalyst or additive, and in the reaction, a substrate compound II undergoes an enol interconversion process under the irradiation of ultraviolet light to generate a hydroxyphthaline intermediate which is then captured by isatin which is cheap and easy to obtain, so that a corresponding target product is obtained. The reaction of the preparation method has good functional group tolerance and wide substrate range, can synthesize various 3-alkyl-3-hydroxyindole-2-ketone compounds and derivatives thereof, has high yield, and shows huge synthesis potential in organic synthesis.
Finally, the above embodiments are only intended to illustrate the technical solutions of the present invention and not to limit the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.
Claims (9)
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