CN115925611A - Fluoroalkyl substituted indole derivative and synthesis method thereof - Google Patents
Fluoroalkyl substituted indole derivative and synthesis method thereof Download PDFInfo
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- CN115925611A CN115925611A CN202211541681.3A CN202211541681A CN115925611A CN 115925611 A CN115925611 A CN 115925611A CN 202211541681 A CN202211541681 A CN 202211541681A CN 115925611 A CN115925611 A CN 115925611A
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- substituted indole
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- 150000002475 indoles Chemical class 0.000 title claims abstract description 45
- 125000003709 fluoroalkyl group Chemical group 0.000 title claims abstract description 11
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 56
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 32
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000000758 substrate Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 17
- 229940054051 antipsychotic indole derivative Drugs 0.000 claims abstract description 16
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 claims abstract description 12
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- -1 chloro (pentamethylcyclopentadiene) ruthenium (II) Chemical compound 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 11
- 239000003208 petroleum Substances 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000009835 boiling Methods 0.000 claims description 9
- 239000003480 eluent Substances 0.000 claims description 9
- 238000010898 silica gel chromatography Methods 0.000 claims description 9
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 3
- TXPVQASIALYEDY-UHFFFAOYSA-L Cl[Ru](C1=C(C=C(C=C1)C)C(C)C)(C1=C(C=C(C=C1)C)C(C)C)Cl Chemical compound Cl[Ru](C1=C(C=C(C=C1)C)C(C)C)(C1=C(C=C(C=C1)C)C(C)C)Cl TXPVQASIALYEDY-UHFFFAOYSA-L 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003570 air Substances 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 238000013375 chromatographic separation Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 8
- 238000002360 preparation method Methods 0.000 abstract description 10
- 238000010189 synthetic method Methods 0.000 abstract description 9
- 238000010276 construction Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 125000001041 indolyl group Chemical group 0.000 description 7
- 238000005259 measurement Methods 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- LDXDSHIEDAPSSA-OAHLLOKOSA-N Ramatroban Chemical compound N([C@@H]1CCC=2N(C3=CC=CC=C3C=2C1)CCC(=O)O)S(=O)(=O)C1=CC=C(F)C=C1 LDXDSHIEDAPSSA-OAHLLOKOSA-N 0.000 description 2
- FSQKKOOTNAMONP-UHFFFAOYSA-N acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229950004496 ramatroban Drugs 0.000 description 2
- GZKLJWGUPQBVJQ-UHFFFAOYSA-N sertindole Chemical compound C1=CC(F)=CC=C1N1C2=CC=C(Cl)C=C2C(C2CCN(CCN3C(NCC3)=O)CC2)=C1 GZKLJWGUPQBVJQ-UHFFFAOYSA-N 0.000 description 2
- 229960000652 sertindole Drugs 0.000 description 2
- KCFYEAOKVJSACF-UHFFFAOYSA-N umifenovir Chemical compound CN1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 KCFYEAOKVJSACF-UHFFFAOYSA-N 0.000 description 2
- 229960004626 umifenovir Drugs 0.000 description 2
- ZKPMMGGHAVKPPN-UHFFFAOYSA-N 1-(1-benzylindol-3-yl)ethanone Chemical compound C12=CC=CC=C2C(C(=O)C)=CN1CC1=CC=CC=C1 ZKPMMGGHAVKPPN-UHFFFAOYSA-N 0.000 description 1
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229960004892 acemetacin Drugs 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940124393 anti-influenza virus drug Drugs 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- JLXLOMMCQWMOIX-UHFFFAOYSA-M chlororuthenium;1,2,3,4,5-pentamethylcyclopentane Chemical compound [Ru]Cl.C[C]1[C](C)[C](C)[C](C)[C]1C JLXLOMMCQWMOIX-UHFFFAOYSA-M 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007337 electrophilic addition reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- NXFFJDQHYLNEJK-CYBMUJFWSA-N laropiprant Chemical compound C=1([C@@H](CC(O)=O)CCC=1C=1C=C(F)C=C(C2=1)S(=O)(=O)C)N2CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-CYBMUJFWSA-N 0.000 description 1
- 229950008292 laropiprant Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000007269 microbial metabolism Effects 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—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
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02B—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO BUILDINGS, e.g. HOUSING, HOUSE APPLIANCES OR RELATED END-USER APPLICATIONS
- Y02B20/00—Energy efficient lighting technologies, e.g. halogen lamps or gas discharge lamps
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Indole Compounds (AREA)
Abstract
The invention provides a fluoroalkyl substituted indole derivative and a synthesis method thereof. The synthetic method of the fluoroalkyl-substituted indole derivative comprises the following steps: in a solvent, under the condition of visible light induced ruthenium catalysis, an indole substrate 2 and bromodifluoroacetic acid ethyl ester react to obtain a fluoroalkyl substituted indole derivative; the method has the advantages of easily obtained and stable raw materials, simple preparation method, simple and convenient operation, easily realized reaction conditions, safety, environmental protection, one-step construction of the indole derivatives, less side reactions and high yield of target products.
Description
Technical Field
The invention relates to a fluoroalkyl substituted indole derivative and a synthesis method thereof, belonging to the technical field of new drug synthesis.
Background
Indole and derivatives thereof, as an important nitrogen-containing heterocyclic compound, occupy an important position in drug design and synthesis and are core frameworks of various drug molecules. Currently marketed drugs such as anti-influenza virus drug Arbidol (Arbidol), cardiovascular drug laropiptan (Laropiprant), antipsychotic drug Sertindole (Sertindole), cystic fibrosis drug tizakato (tezacator), rhinitis drug Ramatroban (Ramatroban) and the like all contain indole skeletons.
In recent years, fluorine atoms or fluorine-containing groups (such as trifluoromethyl, difluoromethyl, etc.) are often introduced into drug molecules due to the characteristics of significantly changing the acidity, lipophilicity, metabolic stability, etc. of compounds, which is also a common means for screening new drugs. Numerous studies have shown that fluoroalkyl-modified indole compounds such as rizoxaban (razaxban) and Acemetacin (Acemetacin) analogues, flurincana (flindakoner) and difluoromethyl tryptophan derivatives play an important role in animal health, microbial metabolism, plant growth, etc. However, due to the structural characteristics of the indole compound and the particularity of the fluorine-containing group, the green, efficient and controllable construction of fluoroalkyl indole molecules, especially fluoroalkyl-substituted molecules in the benzene ring region of the indole, under mild conditions is very challenging.
Therefore, a method for preparing fluoroalkyl-substituted indole molecules in a benzene ring region simply, mildly, greenly, efficiently and controllably with high yield is urgently needed to be developed, and a foundation is laid for the synthesis and application of fluoroalkyl-modified indole compound medicines.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a fluoroalkyl substituted indole derivative and a synthesis method thereof. The method has the advantages of easily obtained and stable raw materials, simple preparation method, simple and convenient operation, easily realized reaction conditions, safety, environmental protection, one-step construction of the indole derivatives, less side reactions and high yield of target products.
The technical scheme of the invention is as follows:
a fluoroalkyl-substituted indole derivative having a structure represented by the following formula 1:
according to the present invention, in the compound of formula 1, t bu is tert-butyl, bn is benzyl and Et is ethyl.
The synthesis method of the fluoroalkyl-substituted indole derivative comprises the following steps:
in a solvent, under the condition of visible light induced ruthenium catalysis, an indole substrate 2 and bromodifluoroacetic acid ethyl ester react to obtain a fluoroalkyl substituted indole derivative;
according to the present invention, in the indole substrate 2, t bu is tert-butyl and Bn is benzyl.
According to the invention, the solvent is one or more of Dichloromethane (DCM), dichloroethane (DCE) or toluene; preferably dichloroethane.
Preferably, according to the invention, the ratio between the mass of the indole substrate 2 and the volume of the solvent is between 30 and 60mg/mL.
According to the invention, the light source adopted by the visible light is white light, blue light or green light; preferably blue light.
Preferably, according to the present invention, the ruthenium is one of dichlorobis (4-methylisopropylphenyl) ruthenium (II), chloro (pentamethylcyclopentadienyl) ruthenium (II) tetramer or ruthenium trichloride; preferably bis (4-methylisopropylphenyl) ruthenium (II) dichloride.
Preferably, according to the invention, the molar ratio of ruthenium to indole substrate 2 is between 0.01 and 0.5; preferably 0.1.
According to a preferred embodiment of the present invention, the molar ratio of ethyl bromodifluoroacetate to indole substrate 2 is 1-1.5; preferably 1.1.
According to the invention, the indole substrate 2 can be prepared according to the prior art; see "angelw. Chem. Int.ed.2017,56,3966" for synthetic methods.
According to the invention, the reaction atmosphere is preferably one or the combination of more than two of air, oxygen, nitrogen or argon; preferably nitrogen.
According to the invention, the reaction temperature is preferably room temperature; the reaction time is 100-240min, preferably 120min.
According to the invention, the method for post-treating the reaction solution obtained after the reaction is completed can be carried out according to the prior art. Preferably, the method for post-treating the reaction solution obtained after the completion of the reaction comprises the steps of: carrying out chromatographic separation on the reaction liquid by using a silica gel column to obtain a fluoroalkyl substituted indole derivative; the eluent used for the silica gel column chromatography separation is a mixed solution of petroleum ether and ethyl acetate with the boiling range of 60-90 ℃, wherein the volume ratio of the petroleum ether to the ethyl acetate is 2:1.
The reaction route of the invention is as follows:
wherein, in the indole substrate 2 and the alkyl substituted indole derivative 1, t bu is tert-butyl, bn is benzyl and Et is ethyl.
The invention has the following technical characteristics and beneficial effects:
1. according to the invention, an indole substrate 2 with indole C3-tert-butyl as an auxiliary group is used as a raw material, and the selective difluoroalkylation of indole C6 is realized under the condition of visible light-induced ruthenium catalysis, so that the 6-difluoroacetic acid ethyl ester indole derivative 1 is synthesized. The method has the advantages of easily obtained and stable raw materials, simple preparation method, simple and convenient operation, one-step construction of the indole derivative, mild reaction conditions, easy realization, safety and environmental protection.
2. According to the invention, a tertiary butyryl group is introduced into the C3 position of indole, firstly, the strong electron withdrawing property of the tertiary butyryl group is utilized to change the electron density distribution of each position on an indole ring; secondly, the tertiary butyl is far away from the C4 position in the spatial arrangement due to the large steric hindrance of the tertiary butyl, so that the active C2 position of the indole can be locked by means of the large steric hindrance of the tertiary butyl; thirdly, the carbonyl oxygen has good coordination, so that the carbonyl oxygen can be coordinated with the ruthenium catalyst to guide the ruthenium catalyst to selectively activate the C4 position of the indole, thereby further changing the electron density distribution of each site of the indole ring, and finally enabling the C6 position of the indole to have the most rich electrons with the aid of a solvation effect, so that the C6 position can be subjected to fluoroalkyl radical electrophilic addition reaction with high selectivity.
3. The method provided by the invention is taken as a whole, the reaction substrate structure, the type of ruthenium catalyst, the type of solvent, the type of visible light and other conditions play a synergistic effect, and the excellent effect of the invention is realized under the combined action, so that the method provided by the invention has the advantages of high reaction selectivity, less side reaction and high yield of target products, which can reach more than 80%, and provides a new thought for the synthesis of difluoroalkylated indole derivative drugs.
Detailed Description
The present invention is further illustrated by the following examples. But is not limited thereto.
Meanwhile, the experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
In the examples, indole substrate 2 synthesis methods are described in "angelw chem. Int. Ed.2017,56,3966".
Example 1:
a synthetic method of fluoroalkyl-substituted indole derivatives comprises the following reaction route:
the preparation steps are as follows: indole substrate 2 (87.4 mg,0.3 mmol), bromodifluoroacetic acid ethyl ester 3 (67mg, 0.33mmol) and dichlorobis (4-methylisopropylphenyl) ruthenium (II) (18.4 mg, 0.03mmol) were added to a 25mL reaction tube, and DCE (2 mL) was added and reacted at room temperature under a blue light irradiation under a nitrogen atmosphere for 120min. The resulting reaction liquid was subjected to silica gel column chromatography (eluent: petroleum ether (boiling range 60-90 ℃)/ethyl acetate =2, 1,v/v) to obtain fluoroalkyl-substituted indole derivative 1 (99 mg, yield 80%) as a yellow solid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Characterization data for fluoroalkyl-substituted indole derivative 1:
1 H NMR(400MHz,CDCl 3 )δ8.24(d,J＝8.4Hz,1H),8.02(s,1H),7.84(d,J＝2.4Hz,1H),7.40(m,1H),7.35–7.28(m,2H),7.29–7.24(m,1H),7.21(m,2H),5.51(t,J＝1.0Hz,2H),4.31(q,J＝7.0Hz,2H),1.29(t,J＝7.0Hz,3H),1.21(s,9H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ206.10,164.64,137.36,136.72,133.21,130.21,129.19,128.20,127.95,123.18,123.15,123.12,123.10,123.09,114.26,113.14,109.06,109.03,109.00,62.00,61.97,61.94,51.11,44.25,27.58,13.92.C 24 H 25 F 2 NO 3 HRMS theoretical value of [ M + H ]] + 414.1875; measurement value 414.1880.
Example 2:
a synthetic method of fluoroalkyl-substituted indole derivatives comprises the following reaction route:
the preparation steps are as follows: a25 mL reaction tube was charged with indole substrate 2 (87.4 mg,0.3 mmol), ethyl bromodifluoroacetate 3 (67mg, 0.33mmol), and dichlorobis (4-methylisopropylphenyl) ruthenium (II) (18.4 mg, 0.03mmol), and toluene (2 mL) was added, and the reaction was carried out under blue light irradiation under nitrogen atmosphere at room temperature for 120min. The resulting reaction liquid was subjected to silica gel column chromatography (eluent: petroleum ether (boiling range 60-90 ℃)/ethyl acetate =2, 1,v/v) to obtain fluoroalkyl-substituted indole derivative 1 (85 mg, yield 69%) as a yellow solid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 3:
a synthetic method of fluoroalkyl-substituted indole derivatives comprises the following reaction route:
the preparation steps are as follows: a25 mL reaction tube was charged with indole substrate 2 (87.4 mg,0.3 mmol), ethyl bromodifluoroacetate 3 (67mg, 0.33mmol), and dichlorobis (4-methylisopropylphenyl) ruthenium (II) (18.4 mg, 0.03mmol), DCM (2 mL) was added, and the reaction was carried out under blue light irradiation under nitrogen atmosphere at room temperature for 120min. The obtained reaction liquid was subjected to silica gel column chromatography (eluent: petroleum ether (boiling range 60-90 ℃)/ethyl acetate =2:1,v/v) to obtain fluoroalkyl-substituted indole derivative 1 (93 mg, yield 75%) as a yellow solid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 4:
a synthetic method of fluoroalkyl-substituted indole derivatives comprises the following reaction route:
the preparation steps are as follows: indole substrate 2 (87.4 mg,0.3 mmol), ethyl bromodifluoroacetate 3 (67mg, 0.33mmol), and ruthenium trichloride (6.2 mg, 0.03mmol) were added to a 25mL reaction tube, and DCE (2 mL) was added thereto, and the reaction was carried out under blue light irradiation and under nitrogen protection at room temperature for 120min. The resulting reaction liquid was subjected to silica gel column chromatography (eluent: petroleum ether (boiling range 60-90 ℃)/ethyl acetate =2, 1,v/v) to obtain fluoroalkyl-substituted indole derivative 1 (24.8 mg, yield 20%) as a yellow solid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 5:
a synthetic method of fluoroalkyl-substituted indole derivatives comprises the following reaction route:
the preparation steps are as follows: indole substrate 2 (87.4 mg,0.3 mmol), bromodifluoroacetic acid ethyl ester 3 (91.3 mg, 0.45mmol) and dichlorobis (4-methylisopropylphenyl) ruthenium (II) (18.4 mg, 0.03mmol) were added to a 25mL reaction tube, and DCE (2 mL) was added and reacted at room temperature under blue light irradiation under nitrogen protection for 120min. The obtained reaction liquid was subjected to silica gel column chromatography (eluent: petroleum ether (boiling range 60-90 ℃)/ethyl acetate =2:1,v/v) to obtain fluoroalkyl-substituted indole derivative 1 (100 mg, yield 80%) as a yellow solid. The target product is confirmed by nuclear magnetic resonance spectrum and high-resolution mass spectrometry.
Example 6:
a synthetic method of fluoroalkyl-substituted indole derivatives comprises the following reaction route:
the preparation steps are as follows: a25 mL reaction tube was charged with indole substrate 2 (87.4 mg,0.3 mmol), ethyl bromodifluoroacetate 3 (91.3 mg, 0.45mmol), and dichlorobis (4-methylisopropylphenyl) ruthenium (II) (18.4 mg, 0.03mmol), and DCE (2 mL) was added and reacted at room temperature under white light irradiation under nitrogen atmosphere for 120min. The obtained reaction liquid was subjected to silica gel column chromatography (eluent: petroleum ether (boiling range 60-90 ℃)/ethyl acetate =2:1,v/v) to obtain fluoroalkyl-substituted indole derivative 1 (50 mg, yield 40%) as a yellow solid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Comparative example 1:
a synthetic method of fluoroalkyl-substituted indole derivatives comprises the following reaction route:
the preparation steps are as follows: 3-acetyl-N-benzylindole (74.8mg, 0.3mmol), bromodifluoroacetic acid ethyl ester 3 (67mg, 0.33mmol), dichlorobis (4-methylisopropylphenyl) ruthenium (II) (18.4mg, 0.03mmol) and DCE (2 mL) were added to a 25mL reaction tube and reacted at room temperature under nitrogen irradiation with blue light for 120min. The resulting reaction solution was subjected to silica gel column chromatography (eluent: petroleum ether (boiling range 60-90 ℃)/ethyl acetate =2:1,v/v), and a C6-fluoroalkyl substituted indole product was not obtained.
Claims (10)
1. A fluoroalkyl-substituted indole derivative having a structure represented by the following formula 1:
2. a process for the synthesis of fluoroalkyl substituted indole derivatives according to claim 1, comprising the steps of:
in a solvent, under the condition of visible light induced ruthenium catalysis, indole substrate 2 and bromodifluoroacetic acid ethyl ester react to obtain fluoroalkyl substituted indole derivatives;
3. the method for synthesizing fluoroalkyl-substituted indole derivative according to claim 2, wherein the solvent is one or a combination of two or more of Dichloromethane (DCM), dichloroethane (DCE) or toluene; preferably dichloroethane.
4. The method for synthesizing fluoroalkyl-substituted indole derivatives according to claim 2, wherein the ratio of the mass of the indole substrate 2 to the volume of the solvent is 30 to 60mg/mL.
5. The method for synthesizing fluoroalkyl-substituted indole derivatives according to claim 2, wherein the light source for visible light is white light, blue light or green light; preferably blue light.
6. The method for synthesizing fluoroalkyl-substituted indole derivative according to claim 2, wherein the ruthenium is one of dichlorobis (4-methylisopropylphenyl) ruthenium (II), chloro (pentamethylcyclopentadiene) ruthenium (II) tetramer, or ruthenium trichloride; preferably bis (4-methylisopropylphenyl) ruthenium (II) dichloride.
7. The method for synthesizing fluoroalkyl-substituted indole derivatives according to claim 2, wherein the molar ratio of ruthenium to indole substrate 2 is 0.01 to 0.5; preferably 0.1.
8. The method for synthesizing fluoroalkyl-substituted indole derivatives according to claim 2, wherein the molar ratio of ethyl bromodifluoroacetate to indole substrate 2 is 1-1.5; preferably 1.1.
9. The method for synthesizing fluoroalkyl-substituted indole derivative according to claim 2, wherein the reaction atmosphere is one or a combination of two or more of air, oxygen, nitrogen, and argon; preferably nitrogen;
preferably, the reaction temperature is room temperature; the reaction time is 100-240min, preferably 120min.
10. The method for synthesizing fluoroalkyl-substituted indole derivatives according to claim 2, wherein the post-treatment of the reaction solution after completion of the reaction comprises the steps of: carrying out chromatographic separation on the reaction liquid by using a silica gel column to obtain a fluoroalkyl substituted indole derivative; the eluent used for silica gel column chromatography is a mixed solution of petroleum ether and ethyl acetate with the boiling range of 60-90 ℃, wherein the volume ratio of the petroleum ether to the ethyl acetate is 2:1.
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Non-Patent Citations (5)
| Title |
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| ISAAC CHOI, 等: "Ruthenium(II)-carboxylate-catalyzed C4/C6–H dual alkylations of indoles", 《TETRAHEDRON LETTERS》, vol. 72, pages 153064 * |
| ISAAC CHOI，等: "Recyclable Ruthenium Catalyst for Distal meta-C@H Activation", 《CHEMISTRY—A EUROPEAN JOURNAL》, vol. 26, pages 15290 - 15297 * |
| JAMIE A. LEITCH，等: "Remote C6-Selective Ruthenium-Catalyzed C−H Alkylation of Indole Derivatives via σ‑Activation", 《ACS CATAL.》, vol. 7, pages 2616 * |
| ZHIQIANG PAN, 等: "Photochemical a-carboxyalkylation of tryptophols and tryptamines via C–H functionalization", 《CHEM. COMMUN.》, vol. 56, pages 4930 * |
| 李志清，等: "可见光催化偕二氟烯烃碳-氟键官能化反应的研究进展", 《有机化学》, vol. 41, pages 4192 - 4207 * |
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