CN116063223A - 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound and synthesis method thereof - Google Patents
10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound and synthesis method thereof Download PDFInfo
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- -1 indole compound Chemical class 0.000 title claims abstract description 37
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims description 25
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims description 25
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims description 25
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 229910052751 metal Inorganic materials 0.000 claims abstract description 9
- 239000002184 metal Substances 0.000 claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 65
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 34
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 29
- 230000002194 synthesizing effect Effects 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 239000007848 Bronsted acid Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- FKOASGGZYSYPBI-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)alumanyl trifluoromethanesulfonate Chemical compound [Al+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F FKOASGGZYSYPBI-UHFFFAOYSA-K 0.000 claims description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims description 2
- JKNHZOAONLKYQL-UHFFFAOYSA-K tribromoindigane Chemical compound Br[In](Br)Br JKNHZOAONLKYQL-UHFFFAOYSA-K 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000000758 substrate Substances 0.000 abstract description 4
- IVYPNXXAYMYVSP-UHFFFAOYSA-N Indole-3-carbinol Natural products C1=CC=C2C(CO)=CNC2=C1 IVYPNXXAYMYVSP-UHFFFAOYSA-N 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 238000005481 NMR spectroscopy Methods 0.000 description 57
- 239000000047 product Substances 0.000 description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- 239000012043 crude product Substances 0.000 description 19
- 239000003480 eluent Substances 0.000 description 19
- 239000003208 petroleum Substances 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- 238000004809 thin layer chromatography Methods 0.000 description 19
- 238000002390 rotary evaporation Methods 0.000 description 18
- 238000012512 characterization method Methods 0.000 description 17
- 238000012544 monitoring process Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- XKSQZCFVTJKNNU-UHFFFAOYSA-N [2-(trifluoromethyl)-1h-indol-3-yl]methanol Chemical compound C1=CC=C2C(CO)=C(C(F)(F)F)NC2=C1 XKSQZCFVTJKNNU-UHFFFAOYSA-N 0.000 description 10
- MMIJMYOYKAKQPN-UHFFFAOYSA-N 1-cyclohexyl-n-{[1-(4-methylphenyl)-1h-indol-3-yl]methyl}methanamine Chemical compound C1=CC(C)=CC=C1N1C2=CC=CC=C2C(CNCC2CCCCC2)=C1 MMIJMYOYKAKQPN-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 150000002475 indoles Chemical class 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- KLRHPHDUDFIRKB-UHFFFAOYSA-M indium(i) bromide Chemical compound [Br-].[In+] KLRHPHDUDFIRKB-UHFFFAOYSA-M 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- OJLPWVOWEHJINA-UHFFFAOYSA-N 2,2,2-trifluoro-1-(1h-indol-3-yl)ethanol Chemical compound C1=CC=C2C(C(O)C(F)(F)F)=CNC2=C1 OJLPWVOWEHJINA-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- DOZCTPAUYJQGBD-UHFFFAOYSA-N indeno[1,2-b]indole Chemical class C1=CC=C2C=C3C4=CC=CC=C4N=C3C2=C1 DOZCTPAUYJQGBD-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 238000006783 Fischer indole synthesis reaction Methods 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000006147 Japp-Klingemann synthesis reaction Methods 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000013086 organic photovoltaic Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
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- 239000002243 precursor Substances 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
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- 235000013599 spices Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a 10-perfluoroalkyl-5, 10-dihydro-indeno [1,2-b ] indole compound and a synthesis method thereof, wherein a perfluoroalkyl 3-indole methanol compound is used as a raw material, and the raw material reacts in a solvent under the catalysis of a catalyst to obtain the 10-perfluoroalkyl-5, 10-dihydro-indeno [1,2-b ] indole compound. The method does not need to use a metal catalyst, and has the advantages of available raw materials, mild conditions, high yield, wide substrate range, atom economy and the like.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound and a synthesis method thereof.
Background
Condensed polycyclic indoles are an important class of indole alkaloids, and many of the compounds show various and rich biological activities and have wide application in the fields of medicine, spice, pesticide, pigment, material chemistry and the like. Among them, indeno [1,2-b ] indole derivatives have been widely used as precursors for the total synthesis of many natural products and have been shown to have a wide range of biological activities such as antioxidant, anticancer, human protein kinase CK2 inhibitors and breast cancer drug resistant protein inhibitors. In addition, indeno [1,2-b ] indoles are also used as electron donors in organic photovoltaic and blue light emitting materials due to their electron-rich nature and strong charge transfer capability. However, the synthesis of indeno [1,2-b ] indole compounds has focused mainly on metal-catalyzed ninhydrin cyclization, the Japp-Klingemann reaction in combination with Fischer indole synthesis, and nitro-or amino-promoted intramolecular reduction-tandem cyclization, and the like. However, these methods have many disadvantages such as the use of expensive transition metal catalysts, the need for raw materials in multiple steps and difficult synthesis, and general reaction efficiency.
Fluorine-containing compounds have important applications in the fields of chemistry, medicine, pesticides, functional materials, etc., and at present about 20% of the medicine and 30% of the pesticide molecules contain at least one F atom. The introduction of fluorine atoms or fluorine-containing groups into drug molecules can significantly improve the physicochemical properties and biological activities of the drug, such as metabolic stability, lipophilicity, permeability and interaction with biological targets, and has become a common method for drug screening. The perfluoroalkyl has strong electron withdrawing property, larger steric hindrance, good lipophilicity and stability, and is also an important synthon. Therefore, the development of a simple and efficient synthesis method for realizing the efficient synthesis of perfluoroalkyl indeno [1,2-b ] indole compounds has extremely important significance.
Disclosure of Invention
This section is intended to outline some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section as well as in the description summary and in the title of the application, to avoid obscuring the purpose of this section, the description summary and the title of the invention, which should not be used to limit the scope of the invention.
The present invention has been made in view of the above-mentioned or existing problems occurring in the prior art.
One of the purposes of the invention is to provide a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound, and the 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound prepared by the invention contains multifunctional groups such as perfluoroalkyl, halogen and the like, and can be further structurally modified and chemically converted into various compounds.
In order to solve the technical problems, the invention provides the following technical scheme: a10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound has a structural formula shown in formula (I):
wherein R is 1 One selected from hydrogen, halogen, ester group, sulfonyloxy group, nitro group, cyano group, methoxy group and methyl group;
R 2 one selected from hydrogen, halogen, phenyl, methyl, methoxy and trifluoromethyl;
p is selected from one of P-toluenesulfonyl, benzenesulfonyl, P-methoxybenzenesulfonyl, P-bromobenzenesulfonyl and P-nitrobenzenesulfonyl;
n is selected from 1,2, 3 or 4.
It is another object of the present invention to provide a method for synthesizing 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compounds as described above, which enables efficient synthesis of 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compounds by using inexpensive trifluoromethanesulfonic acid as a catalyst, without using a metal catalyst, and only producing water as the only byproduct. The method has the advantages of easily available raw materials, mild conditions, high yield, wide substrate range, atom economy and the like.
The specific technical scheme is as follows: taking a compound shown in a formula (II) as a raw material, and reacting in a solvent under the catalysis of a catalyst to obtain the compound shown in the formula (I);
wherein R in formula (II) 1 、R 2 P, n and R in formula (I) 1 、R 2 The correspondence between P, n is consistent.
As a preferred embodiment of the method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound of the present invention, wherein: the catalyst is selected from a metal Lewis acid or a Bronsted acid.
As a preferred embodiment of the method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound of the present invention, wherein: the metal Lewis acid comprises scandium triflate, copper triflate, aluminum triflate, ferric trichloride and indium tribromide.
As a preferred embodiment of the method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound of the present invention, wherein: the Bronsted acid comprises one of p-toluenesulfonic acid and trifluoromethanesulfonic acid.
As a preferred embodiment of the method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound of the present invention, wherein: the molar ratio of the catalyst to the compound shown in the formula (II) is 0.1-0.3:1.
As a preferred embodiment of the method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound of the present invention, wherein: the concentration of the compound shown in the formula (II) in the solvent is 0.05-0.2 mol/L.
As a preferred embodiment of the method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound of the present invention, wherein: the solvent comprises one of dichloroethane, toluene and hexafluoroisopropanol.
As a preferred embodiment of the method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound of the present invention, wherein: the solvent is hexafluoroisopropanol.
As a preferred embodiment of the method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound of the present invention, wherein: the reaction temperature is 5-60 ℃ and the reaction time is 0.5-48 hours.
Compared with the prior art, the invention has the following beneficial effects:
the method of the invention uses cheap trifluoromethanesulfonic acid as a catalyst, does not need to use a metal catalyst, only generates water as a unique byproduct, and provides a novel method for synthesizing 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compounds. The method has the advantages of easily available raw materials, mild conditions, high yield, wide substrate range, atom economy and the like.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the description of the embodiments will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art. Wherein:
FIG. 1 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the target product 1a prepared in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the target product 1a prepared in example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance fluorine spectrum of the target product 1a prepared in example 1 of the present invention;
FIG. 4 is a single crystal diffractogram of the target product 1b prepared in example 2 of the present invention.
Detailed Description
In order that the above-recited objects, features and advantages of the present invention will become more apparent, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
Further, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic can be included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
The starting benzenesulfonyl-protected perfluoroalkyl 3-indolemethanol compounds used in the examples were prepared according to the methods reported in the literature (Tetrahedron, 2017,73 (16), 2283-2289;Journal of the American Chemical Society,2002,124 (44): 13179-13184).
Example 1
Taking a 10mL eggplant-shaped bottle, sequentially adding trifluoromethyl 3-indolemethanol 2a (0.15 mmol) protected by tosyl and trifluoromethanesulfonic acid (0.015 mmol), adding hexafluoroisopropanol (1.5 mL) under the atmosphere, reacting for 1h under normal temperature, monitoring the reaction by TLC, removing the solvent by rotary evaporation after the reaction is finished, and separating the crude product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain a target product 1a (63.5 mg, white solid, yield 99%).
The reaction equation is:
the target product 1a is characterized, the nuclear magnetic resonance hydrogen spectrum is shown in fig. 1, the nuclear magnetic resonance carbon spectrum is shown in fig. 2, and the nuclear magnetic resonance fluorine spectrum is shown in fig. 3:
1 H NMR(600MHz,CDCl 3 )δ8.54(d,J＝7.9Hz,1H),8.29(d,J＝8.4Hz,1H),7.69(d,J＝7.7Hz,1H),7.66(d,J＝8.4Hz,1H),7.62(d,J＝7.7Hz,1H),7.54(t,J＝7.7Hz,1H),7.39–7.34(m,2H),7.31(t,J＝7.3Hz,1H),7.11(d,J＝8.3Hz,2H),4.45(q,J＝8.6Hz,1H),2.27(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ145.1,144.6,141.1,140.8,134.8,134.8,129.8,129.5,126.8,126.6,125.9(q,J＝278.9Hz),125.8,125.7,125.1,124.6,124.4(q,J＝2.4Hz),122.5,119.8,115.6,45.9(q,J＝30.9Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-67.18(d,J＝8.6Hz,3F).
example 2
10mL eggplant-shaped bottle is taken, benzenesulfonyl-protected trifluoromethyl 3-indolemethanol 2b (0.15 mmol) and trifluoromethanesulfonic acid (0.015 mmol) are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 1h under normal temperature, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain the target product 1b (61.4 mg, white solid, yield 99%).
The reaction equation is:
characterization of the above target product 1 b:
1 H NMR(600MHz,CDCl 3 )δ8.54(d,J＝7.9Hz,1H),8.30(d,J＝8.4Hz,1H),7.78(d,J＝7.6Hz,2H),7.69(d,J＝7.5Hz,1H),7.62(d,J＝7.7Hz,1H),7.55(t,J＝7.7Hz,1H),7.45(t,J＝7.5Hz,1H),7.37(t,J＝7.7Hz,2H),7.32(t,J＝7.8Hz,3H),4.46(q,J＝8.6Hz,1H)；
13 C NMR(150MHz,CDCl 3 )δ144.6,141.0,140.8,137.6,134.7,133.9,129.5,129.2,126.8,126.5,125.9(q,J＝279.1Hz),125.8,125.8,125.2,124.7,122.4,119.9,115.6,45.9(q,J＝30.7Hz)；
19 F NMR(565MHz,CDCl 3 )δ-67.16(d,J＝8.7Hz,3F).
the structure of compound 1b was confirmed by single crystal diffraction, as shown in fig. 4.
Example 3
Taking a 10mL eggplant-shaped bottle, sequentially adding trifluoromethyl 3-indolemethanol 2c (0.15 mmol) protected by p-nitrobenzenesulfonyl and trifluoromethanesulfonic acid (0.015 mmol), adding hexafluoroisopropanol (1.5 mL) under the atmosphere, reacting for 4h under normal temperature, monitoring the reaction by TLC, removing the solvent by rotary evaporation after the reaction is finished, and separating the crude product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain a target product 1c (53.1 mg, yellow solid, yield 85%).
The reaction equation is:
characterization of the above target product 1 c:
1 H NMR(600MHz,CDCl 3 )δ8.46(d,J＝7.9Hz,1H),8.25(d,J＝8.4Hz,1H),8.14(d,J＝8.9Hz,2H),7.90(d,J＝8.9Hz,2H),7.70(d,J＝7.5Hz,1H),7.61(d,J＝7.7Hz,1H),7.55(t,J＝7.7Hz,1H),7.39(t,J＝7.8Hz,2H),7.37–7.32(m,1H),4.46(q,J＝8.5Hz,1H)；
13 C NMR(150MHz,CDCl 3 )δ150.6,144.4,142.4,141.0,140.7,134.3,129.7,127.9,127.2,126.12,126.1(q,J＝2.6Hz),126.0,125.8,125.7(q,J＝279.3Hz),125.5,124.4,122.2,120.3,115.7,46.0(q,J＝31.3Hz)；
19 F NMR(565MHz,CDCl 3 )δ-67.19(d,J＝8.5Hz,3F).
example 4
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2d (0.15 mmol) and trifluoromethanesulfonic acid (0.015 mmol) are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 2h under normal temperature, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain the target product 1d (69.0 mg, white solid, yield 98%).
The reaction equation is:
characterization of the above target product 1 d:
1 H NMR(600MHz,CDCl 3 )δ8.52(d,J＝7.9Hz,1H),8.20(dd,1H),7.65(d,J＝7.5Hz,1H),7.62(d,J＝8.4Hz,2H),7.53(t,J＝7.7Hz,1H),7.37(td,J＝7.6,0.7Hz,1H),7.29–7.26(m,1H),7.23(t,J＝8.1Hz,1H),7.10(d,J＝8.2Hz,2H),4.71(q,J＝7.4Hz,1H),2.27(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ146.3,145.5,142.4,141.5,134.3,134.1,129.8,129.5,127.1,126.6,126.0,125.6,125.5,125.3,125.1(q,J＝280.7Hz),124.9,123.4(q,J＝1.8Hz),122.8,114.2,46.6(q,J＝29.8Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-66.10(d,J＝7.4Hz,3F).
example 5
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2e (0.15 mmol) and trifluoromethanesulfonic acid (0.015 mmol) are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 2h under normal temperature, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/20, V/V) to obtain the target product 1e (75.4 mg, white solid, yield 99%).
The reaction equation is:
characterization of the above target product 1 e:
1 H NMR(600MHz,CDCl 3 )δ8.52(d,J＝7.9Hz,1H),8.33–8.27(m,2H),8.03(d,J＝8.1Hz,1H),7.69(d,J＝7.5Hz,1H),7.66(d,J＝8.3Hz,2H),7.54(t,J＝7.6Hz,1H),7.38(t,J＝7.5Hz,1H),7.12(d,J＝8.2Hz,2H),4.48(q,J＝8.4Hz,1H),3.93(s,3H),2.27(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ166.8,145.9,145.5,143.2,141.1,134.5,134.3,130.0,129.6,127.2,126.6,126.5,126.1,125.8,125.7(q,J＝278.8Hz),125.5,124.2,122.6,121.7,115.2,52.2,45.9(q,J＝30.6Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-67.14(d,J＝8.5Hz,3F).
example 6
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolyl methanol 2f (0.15 mmol) and trifluoromethane sulfonic acid (0.015 mmol) are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 5h under normal temperature, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/50-1/5, V/V) to obtain the target product 1f (107.7 mg, white solid, yield 90%).
The reaction equation is:
characterization of the above target product 1 f:
1 H NMR(600MHz,CDCl 3 )δ8.50(d,J＝7.9Hz,1H),8.17(d,J＝9.1Hz,1H),7.68(d,J＝8.3Hz,2H),7.66(d,J＝7.6Hz,1H),7.63(d,J＝8.4Hz,2H),7.53(t,J＝7.7Hz,1H),7.38(t,J＝7.6Hz,1H),7.28(d,J＝8.1Hz,2H),7.15(d,J＝8.3Hz,2H),7.10(d,J＝1.9Hz,1H),7.01(dd,J＝9.1,2.4Hz,1H),4.36(q,J＝8.5Hz,1H),2.44(s,3H),2.30(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ146.6,146.1,145.5,145.5,141.0,138.8,134.6,134.3,132.0,130.0,129.7,129.6,128.5,127.3,126.6,126.2,125.8,125.5(q,J＝250.5Hz),123.5(q,J＝1.7Hz),122.7,119.4,116.4,113.4,45.8(q,J＝30.1Hz),21.6,21.5；
19 F NMR(565MHz,CDCl 3 )δ-67.29(d,J＝8.4Hz,3F).
example 7
10mL eggplant-shaped bottle is taken, 2g (0.15 mmol) of trifluoromethyl 3-indolyl methanol and 0.045 mmol) of trifluoromethane sulfonic acid are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 12h under normal temperature, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/50-1/25, V/V) to obtain 1g (61.1 mg, white solid, yield 90%).
The reaction equation is:
characterization of the above target product 1 g:
1 H NMR(600MHz,CDCl 3 )δ8.53(d,J＝7.9Hz,1H),8.36(d,J＝8.8Hz,1H),7.92(s,1H),7.71(d,J＝7.5Hz,1H),7.67(d,J＝8.3Hz,2H),7.60–7.54(m,2H),7.42(t,J＝7.5Hz,1H),7.17(d,J＝8.2Hz,2H),4.49(q,J＝8.4Hz,1H),2.31(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ146.7,146.0,142.2,141.2,134.4,133.8,130.2,129.7,127.8,126.6,126.0,125.7,124.7,124.6(q,J＝1.0Hz),124.4,122.9,119.0,116.2,108.3,45.9(q,J＝31.2Hz),21.6；
19 F NMR(565MHz,CDCl 3 )δ-67.19(d,J＝8.5Hz,3F).
example 8
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2h (0.15 mmol) and trifluoromethanesulfonic acid (0.015 mmol) are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 2.5h under normal temperature, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/30, V/V) to obtain the target product 1h (67.7 mg, white solid, yield 99%).
The reaction equation is:
characterization of the above target product 1 h:
1 H NMR(600MHz,CDCl 3 )δ8.50(d,J＝7.7Hz,1H),8.10(s,1H),7.66(d,J＝7.4Hz,3H),7.52(t,J＝7.5Hz,1H),7.49(d,J＝7.8Hz,1H),7.34(t,J＝7.3Hz,1H),7.18–7.05(m,3H),4.42(q,J＝8.2Hz,1H),2.52(s,3H),2.28(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ145.0,143.9,141.3,140.9,135.4,135.0,134.9,129.8,129.4,126.5,126.4,126.0,125.9(q,J＝278.7Hz),125.7,124.5(q,J＝2.8Hz),123.5,122.2,119.4,115.7,45.9(q,J＝31.0Hz),22.1,21.5；
19 F NMR(565MHz,CDCl 3 )δ-67.21(d,J＝8.7Hz,3F).
example 9
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2i (0.15 mmol) and trifluoromethanesulfonic acid (0.015 mmol) are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 3h under normal temperature, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain the target product 1i (46.3 mg, light yellow solid, yield 70%).
The reaction equation is:
characterization of the above target product 1 i:
1 H NMR(600MHz,CDCl 3 )δ8.26(d,J＝7.8Hz,1H),7.59(d,J＝7.5Hz,1H),7.51(t,J＝7.6Hz,1H),7.32(t,J＝7.5Hz,1H),7.28(d,J＝7.5Hz,1H),7.22(t,J＝7.5Hz,1H),7.19–7.16(m,3H),6.92(d,J＝8.2Hz,2H),4.26(q,J＝8.7Hz,1H),2.79(s,3H),2.23(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ149.3,144.7,143.3,140.3,136.2,132.4,130.5,129.6,129.5(q,J＝2.7Hz),129.2,129.1,128.9,126.6,126.6,126.0,125.7(q,J＝304.3Hz),125.4,122.9,117.4,46.1(q,J＝30.9Hz),21.7,21.4；
19 F NMR(565MHz,CDCl 3 )δ-66.95(d,J＝8.8Hz,3F).
example 10
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2j (0.15 mmol) and trifluoromethanesulfonic acid (0.015 mmol) are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 5h under normal temperature, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/30, V/V) to obtain the target product 1j (70.1 mg, white solid, yield 91%).
The reaction equation is:
characterization of the above target product 1 j:
1 H NMR(600MHz,CDCl 3 )δ8.82(s,1H),8.29(d,J＝8.3Hz,1H),7.75(t,J＝8.1Hz,3H),7.68(d,J＝8.4Hz,2H),7.63(d,J＝7.7Hz,1H),7.61(dd,J＝7.9,1.4Hz,1H),7.52(t,J＝7.7Hz,2H),7.42(t,J＝7.4Hz,1H),7.37(t,J＝7.3Hz,1H),7.33(t,J＝7.3Hz,1H),7.12(d,J＝8.2Hz,2H),4.51(q,J＝8.5Hz,1H),2.27(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ145.2,144.4,142.6,140.9,140.8,140.0,135.5,134.8,129.9,128.9,127.7,127.4,126.6,125.9,125.8,125.6,125.2,125.0(q,J＝2.0Hz),124.6,121.3,119.9,115.7,45.8(q,J＝31.0Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-67.13(d,J＝8.6Hz,3F).
example 11
10mL eggplant-shaped bottle is taken, trifluoromethyl 3-indolemethanol 2k (0.15 mmol) and trifluoromethanesulfonic acid (0.015 mmol) are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 10h under normal temperature, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/30, V/V) to obtain the target product 1k (49.8 mg, white solid, yield 67%).
The reaction equation is:
characterization of the above target product 1 k:
1 H NMR(600MHz,CDCl 3 )δ8.78(s,1H),8.28(d,J＝8.4Hz,1H),7.77(d,J＝7.8Hz,1H),7.63(d,J＝8.1Hz,4H),7.40(t,J＝7.8Hz,1H),7.34(t,J＝7.5Hz,1H),7.14(d,J＝8.2Hz,2H),4.52(q,J＝8.4Hz,1H),2.29(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ145.5,144.5,143.1,141.0,135.6,134.6,132.0(q,J＝32.2Hz),130.0,126.6,125.9,125.8,125.6(q,J＝2.3Hz),125.5(q,J＝279.5Hz),125.3,124.8,124.1(q,J＝272.9Hz),123.7(dd,J＝7.5,3.8Hz),120.1,119.3(q,J＝3.9Hz),115.6,46.1(q,J＝31.7Hz),21.5；
19 F NMR(565MHz,CDCl 3 )δ-62.34(s,3F),-66.94(d,J＝8.5Hz,3F).
example 12
10mL eggplant-shaped bottle is taken, 2L (0.15 mmol) of trifluoromethyl 3-indolyl methanol and 0.015 mmol) of trifluoromethane sulfonic acid are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 3.5h under normal temperature, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/30, V/V) to obtain 1L (48.0 mg, white solid, yield 68%).
The reaction equation is:
characterization of the above target product 1 l:
1 H NMR(600MHz,CDCl 3 )δ8.32(d,J＝8.0Hz,1H),7.83(d,J＝2.2Hz,1H),7.64(d,J＝8.4Hz,2H),7.48–7.42(m,2H),7.30(d,J＝8.0Hz,1H),7.11(d,J＝8.2Hz,2H),6.92(dd,J＝8.6,2.3Hz,1H),4.35(q,J＝8.7Hz,1H),3.91(s,3H),2.45(s,3H),2.27(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ158.0,145.0,143.4,141.8,140.9,136.3,134.8,132.5,129.9,129.8,126.6,126.5,126.0(q,J＝279.2Hz),123.8(q,J＝2.5Hz),121.5,120.1,119.9,113.2,100.4,55.8,45.7(q,J＝30.9Hz),21.5,21.4；
19 F NMR(565MHz,CDCl 3 )δ-67.29(d,J＝8.7Hz,3F).
example 13
10mL eggplant-shaped bottle is taken, pentafluoroethyl 3-indolemethanol 2m (0.15 mmol) and trifluoromethanesulfonic acid (0.015 mmol) are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 0.5h under normal temperature, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain the target product 1m (71.0 mg, yellow solid, yield 99%).
The reaction equation is:
characterization of the above target product 1 m:
1 H NMR(600MHz,CDCl 3 )δ8.55(d,J＝7.9Hz,1H),8.29(d,J＝8.4Hz,1H),7.67(d,J＝7.1Hz,1H),7.59(d,J＝8.2Hz,3H),7.53(t,J＝7.7Hz,1H),7.35(dd,J＝13.2,6.9Hz,2H),7.31(t,J＝7.4Hz,1H),7.07(d,J＝8.2Hz,2H),4.49(t,J＝10.8Hz,1H),2.26(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ145.0,144.4,141.0,140.7(d,J＝9.7Hz),134.6,134.5,129.6,129.4,126.6,126.5,126.1,126.0(d,J＝4.1Hz),125.2,124.8,124.7,122.5,119.8(d,J＝6.1Hz),115.8,45.2(t,J＝24.7Hz),21.4,carbon signals corresponding to the C 2 F 5 group cannot be identified due to C-F coupling；
19 F NMR(565MHz,CDCl 3 )δ-80.29–-80.45(m,3F),-105.04–-105.69(m,1F),-108.96–-109.56(m,1F).
example 14
A10 mL eggplant-shaped bottle is taken, heptafluoropropyl 3-indolemethanol 2n (0.15 mmol) and trifluoromethanesulfonic acid (0.015 mmol) are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 2h under normal temperature conditions, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain the target product 1n (71.5 mg, yellow solid, yield 90%).
The reaction equation is:
characterization of the above target product 1 n:
1 H NMR(600MHz,CDCl 3 )δ8.54(d,J＝7.9Hz,1H),8.30(d,J＝8.4Hz,1H),7.67(d,J＝7.4Hz,1H),7.57(d,J＝8.3Hz,3H),7.53(t,J＝7.7Hz,1H),7.39–7.28(m,3H),7.06(d,J＝8.3Hz,2H),4.50(t,J＝11.5Hz,1H),2.24(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ145.0,144.5,141.1,140.7(dd,J＝9.4,1.6Hz),134.5,129.6,129.3,126.6,126.5,126.3,125.9(d,J＝2.8Hz),125.2,124.9(dd,J＝10.7,1.7Hz),124.8,122.5,119.8(d,J＝5.9Hz),116.0,46.1(t,J＝25.0Hz),21.3,carbon signals correspondingto the C 3 F 7 group cannot be identified due to C-F coupling；
19 F NMR(565MHz,CDCl 3 )δ-81.10(t,J＝10.9Hz,3F),-101.40–-102.05(m,1F),-106.09–-106.71(m,1F),-123.62(ddd,J＝289.5,14.6,7.6Hz,1F),-124.88(ddd,J＝289.7,14.8,5.3Hz,1F).
example 15
A10 mL eggplant-shaped bottle is taken, nonafluorobutyl 3-indolemethanol 2o (0.15 mmol) and trifluoromethanesulfonic acid (0.015 mmol) are sequentially added, hexafluoroisopropanol (1.5 mL) is added under the atmosphere, the reaction is carried out for 2h under normal temperature conditions, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/80, V/V) to obtain the target product 1o (85.5 mg, yellow solid, yield 96%).
The reaction equation is:
characterization of the above target product 1 o:
1 H NMR(600MHz,CDCl 3 )δ8.54(d,J＝7.6Hz,1H),8.31(d,J＝8.1Hz,1H),7.67(d,J＝6.5Hz,1H),7.61–7.49(m,4H),7.40–7.28(m,3H),7.04(d,J＝7.7Hz,2H),4.50(t,J＝11.6Hz,1H),2.23(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ145.0,144.5,141.2,140.7(d,J＝8.8Hz),134.5,129.6,129.3,126.6,126.5,126.3,125.9(d,J＝3.3Hz),125.2,125.0(d,J＝10.1Hz),124.8,122.5,119.8(d,J＝6.1Hz),116.0,46.4(t,J＝25.1Hz),21.3,carbon signals correspondingto the C 4 F 9 group cannot be identified due to C-F coupling；
19 F NMR(565MHz,CDCl 3 )δ-81.02(t,J＝9.0Hz,3F),-100.27–-101.07(m,1F),-105.58–-106.50(m,1F),-120.12–-120.76(m,1F),-121.01–-121.67(m,1F),-125.37–-126.05(m,1F),-126.60–-127.29(m,1F).
example 16
In order to verify the potential industrial scale-up application of the present invention, a ten gram scale-up experiment was also performed, as follows.
A250 mL round bottom flask is taken, trifluoromethyl 3-indolemethanol 2a (22.5 mmol,10.023 g) and trifluoromethanesulfonic acid (2.25 mmol) are sequentially added, hexafluoroisopropanol (75 mL) is added under the atmosphere, the reaction is carried out for 2h under normal temperature conditions, TLC monitoring is carried out, after the reaction is finished, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100-1/50, V/V) to obtain a target product 1a (9.487 g, white solid, yield 98%).
The reaction equation is:
it can be seen that when the trifluoromethyl 3-indolemethanol 2a serving as a raw material is amplified to 22.5mmol (10.023 g), the expected product can still be obtained in 98% yield when the loading of the trifluoromethanesulfonic acid catalyst is 10mol%, so that the invention is fully shown to be applicable to industrial application.
Example 17
Examples 1-16 the 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compounds prepared may be further structurally modified and chemically converted to various compounds as intermediates. The present example performs the following experiments:
a10 mL round bottom flask was taken, 10-trifluoromethyl-5, 10-indano [1,2-b ] indole compound 1a (0.3 mmol) was dissolved in dry dichloroethane (3 mL) under atmospheric conditions, then trifluoromethanesulfonic acid (2.1 mmol) was added and reacted at room temperature for 0.5h (thin layer chromatography was followed until reaction was complete), after the reaction was completed, 2mL saturated sodium bicarbonate was added to quench, ethyl acetate was extracted twice, the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by rotary evaporation, and the crude product was separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/100 to 1/30, V/V) to give Ts 3 (65.6 mg, white solid, yield 45%).
Characterization of the above target product 3:
1 H NMR(600MHz,CDCl 3 )δ8.39(s,1H),7.74(dd,J＝5.5,3.1Hz,1H),7.70(d,J＝7.5Hz,1H),7.44–7.38(m,3H),7.32–7.28(m,1H),7.27–7.23(m,2H),4.51(q,J＝8.8Hz,1H)；
13 C NMR(150MHz,CDCl 3 )δ144.3,141.9(q,J＝2.2Hz),140.5,135.2,128.7,126.6(q,J＝278.4Hz),126.1,126.0,124.1,122.4,121.1,119.3,117.9,116.0(q,J＝3.0Hz),112.2,46.5(q,J＝30.9Hz)；
19 F NMR(565MHz,CDCl 3 )δ-67.73(d,J＝8.8Hz,3F).
it can be seen that, taking 10-trifluoromethyl-5, 10-indano [1,2-b ] indole compound 1a prepared in example 16 as an example, p-toluenesulfonyl protecting group can be removed by trifluoromethanesulfonic acid catalysis to obtain a product 3, the reaction equation is as follows:
example 18
Examples 1-16 the 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compounds prepared may be further structurally modified and chemically converted to various compounds as intermediates. The present example performs the following experiments:
a25 mL round bottom flask was taken, 10-trifluoromethyl-5, 10-indano [1,2-b ] indole compound 1a (0.3 mmol) was dissolved in methanol (10 mL) under atmospheric conditions, magnesium turnings (6.0 mmol) were added, the reaction was carried out under ultrasonic conditions for 5h (thin layer chromatography was followed until the reaction was complete), dilute hydrochloric acid (0.5M) was added dropwise after the reaction was completed for quenching, dichloromethane extraction was carried out twice, the organic phases were combined, saturated sodium bicarbonate solution was washed, the organic phase was dried over anhydrous magnesium sulfate, the solvent was removed by filtration and spin-concentration, and the crude product was isolated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/50 to 1/8,V/V) to give product 4 (103.6 mg, yellow solid, yield 80%).
Characterization of the above target product 4:
1 H NMR(600MHz,CDCl 3 )δ8.53(d,J＝7.8Hz,1H),8.31(d,J＝8.0Hz,1H),7.97(d,J＝7.7Hz,1H),7.92(d,J＝7.5Hz,1H),7.63(d,J＝8.0Hz,2H),7.35(t,J＝7.6Hz,1H),7.32–7.27(m,3H),7.05(d,J＝8.1Hz,2H),4.02(s,3H),4.01(s,3H),2.24(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ159.6,144.4,141.4,139.3,138.7,135.0,130.0,129.6,126.6,125.8,125.7,125.2,124.7,124.2,124.0,123.0,121.5,121.0,115.6,97.8,57.7,57.6,21.4.
it can be seen that, taking 10-trifluoromethyl-5, 10-indano [1,2-b ] indole compound 1a prepared in example 16 as an example, 10-trifluoromethyl-5, 10-indano [1,2-b ] indole compound 1a can be selectively defluorinated and methoxylated by magnesium chips and methanol under ultrasonic conditions to obtain a product 4, and the reaction equation is as follows:
example 19
Examples 1-16 the 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compounds prepared may be further structurally modified and chemically converted to various compounds as intermediates. The present example performs the following experiments:
10mL round bottom flask was taken, 10-trifluoromethyl-5, 10-indano [1,2-b ] indole compound 1a (0.3 mmol), sodium hydroxide (2.1 mmol) and methanol (3 mL) were added under atmospheric conditions, the reaction was followed by 2.5h under reflux (thin layer chromatography followed by reaction until completion), after completion of the reaction, 2mL saturated ammonium chloride solution was added, dichloromethane extraction was twice, the organic phases were combined, the saturated sodium chloride solution was washed, the organic phases were dried over anhydrous magnesium sulfate, filtered and the solvent was removed by rotary evaporation, and the crude product was isolated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1/50 to 1/6, V/V) to give product 5 (80.0 mg, white solid, 96% yield).
Characterization of the above target product 5:
1 H NMR(600MHz,CDCl 3 )δ8.64(s,1H),7.68–7.63(m,1H),7.54(d,J＝7.3Hz,1H),7.37–7.34(m,1H),7.32–7.27(m,2H),7.23(td,J＝7.3,1.2Hz,1H),7.18(dd,J＝6.0,3.1Hz,2H),3.69(s,3H),3.12(s,3H)；
13 C NMR(150MHz,DMSO)δ166.4,143.2,140.8,136.1,130.1,125.0,122.1,120.0,119.3,117.1,116.1,114.0,114.0,113.0,108.4,74.7,47.8,47.7.
it can be seen that, taking 10-trifluoromethyl-5, 10-indano [1,2-b ] indole compound 1a prepared in example 16 as an example, 10-trifluoromethyl-5, 10-indano [1,2-b ] indole compound 1a can also be catalyzed by sodium hydroxide, and product 5 is obtained under heating reflux in methanol solution, and the reaction equation is as follows:
example 20
On the basis of example 1, the reaction conditions such as acid catalyst, solvent and reaction time were optimized, and the specific optimization results are shown in the following table 1:
TABLE 1
| Catalyst (10 mol%) | Solvent (0.1M) | Time (h) | Yield (%) | |
| 1 | Sc(OTf) 3 | PhMe | 24 | - |
| 2 | Sc(OTf) 3 | DCE | 24 | - |
| 3 | Sc(OTf) 3 | HFIP | 5 | 77 |
| 4 | Cu(OTf) 2 | HFIP | 12 | 94 |
| 5 | Al(OTf) 3 | HFIP | 15 | 91 |
| 6 | FeCl 3 | HFIP | 48 | 87 |
| 7 | InBr 3 | HFIP | 48 | 96 |
| 8 | TsOH | HFIP | 6 | 97 |
| 9 | TfOH | HFIP | 1 | 99 |
| 10 | TfOH | DCE | 24 | 17 |
| 11 | TfOH | PhMe | 24 | 10 |
| 12 | TfOH | THF | 24 | NR |
| 13 | - | HFIP | 24 | NR |
As can be seen from the data in Table 1, sc (OTf) was first used in toluene and 1, 2-dichloroethane at ambient temperature 3 (10 mol%) as catalyst, no reaction occurred. While using Hexafluoroisopropanol (HFIP) as solvent, the desired product 1a was obtained in 77% isolated yield. Other metal Lewis acid catalysts, e.g. Cu (OTf) 2 、Al(OTf) 3 、FeCl 3 InBr (InBr) 3 1a was likewise obtained in 87-96% yield. When using bronsted acid p-toluene sulfonic acid (TsOH) and trifluoromethane sulfonic acid (TfOH), the expected product 1a is obtained in excellent yields, with trifluoromethane sulfonic acid (TfOH) being the most effective as a catalyst. With trifluoromethanesulfonic acid (TfOH) as a catalyst, in other common solvents such as dichloroethane, toluene and tetrahydrofuran, the effect is very poor or even non-reactive. The blank test showed that no reaction occurred without catalyst.
The method of the invention uses cheap trifluoromethanesulfonic acid as a catalyst, does not need to use a metal catalyst, only generates water as a unique byproduct, and realizes the efficient synthesis of the 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound. The method has the advantages of easily available raw materials, mild conditions, wide substrate range, high yield, atom economy and the like.
It should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered in the scope of the claims of the present invention.
Claims (10)
1. A 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound characterized in that: the structural formula is shown as formula (I):
wherein R is 1 One selected from hydrogen, halogen, ester group, sulfonyloxy group, nitro group, cyano group, methoxy group and methyl group;
R 2 one selected from hydrogen, halogen, phenyl, methyl, methoxy and trifluoromethyl;
p is selected from one of P-toluenesulfonyl, benzenesulfonyl, P-methoxybenzenesulfonyl, P-bromobenzenesulfonyl and P-nitrobenzenesulfonyl;
n is selected from 1,2, 3 or 4.
2. The method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound according to claim 1, wherein: taking a compound shown in a formula (II) as a raw material, and reacting in a solvent under the catalysis of a catalyst to obtain the compound shown in the formula (I);
wherein R in formula (II) 1 、R 2 P, n and R in formula (I) 1 、R 2 The correspondence between P, n is consistent.
3. The method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound according to claim 2, wherein: the catalyst is selected from a metal Lewis acid or a Bronsted acid.
4. A process for the synthesis of a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound according to claim 3, wherein: the metal Lewis acid comprises scandium triflate, copper triflate, aluminum triflate, ferric trichloride and indium tribromide.
5. A process for the synthesis of a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound according to claim 3, wherein: the Bronsted acid comprises one of p-toluenesulfonic acid and trifluoromethanesulfonic acid.
6. The method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound according to any one of claims 2 to 5, wherein: the molar ratio of the catalyst to the compound shown in the formula (II) is 0.1-0.3:1.
7. The method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound according to any one of claims 2 to 5, wherein: the concentration of the compound shown in the formula (II) in the solvent is 0.05-0.2 mol/L.
8. The method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound according to claim 7, wherein: the solvent comprises one of dichloroethane, toluene and hexafluoroisopropanol.
9. The method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound according to claim 8, wherein: the solvent is hexafluoroisopropanol.
10. The method for synthesizing a 10-perfluoroalkyl-5, 10-indano [1,2-b ] indole compound according to any one of claims 2 to 5, 8, 9, wherein: the reaction temperature is 5-60 ℃ and the reaction time is 0.5-48 hours.
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