CN116082214A - 2-aryl-3-tert-butylindole compound, preparation method and application thereof - Google Patents
2-aryl-3-tert-butylindole compound, preparation method and application thereof Download PDFInfo
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- CN116082214A CN116082214A CN202310161075.7A CN202310161075A CN116082214A CN 116082214 A CN116082214 A CN 116082214A CN 202310161075 A CN202310161075 A CN 202310161075A CN 116082214 A CN116082214 A CN 116082214A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- -1 disubstituted indole compound Chemical class 0.000 claims abstract description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 239000003960 organic solvent Substances 0.000 claims description 21
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 20
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 19
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 19
- 150000002475 indoles Chemical class 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 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 description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 125000004185 ester group Chemical group 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 230000000975 bioactive effect Effects 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 7
- 238000013508 migration Methods 0.000 abstract description 5
- 230000005012 migration Effects 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 61
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 239000003208 petroleum Substances 0.000 description 29
- 238000004440 column chromatography Methods 0.000 description 16
- 239000003480 eluent Substances 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 13
- 238000010791 quenching Methods 0.000 description 13
- 230000000171 quenching effect Effects 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- 238000010200 validation analysis Methods 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000002994 raw material Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- PSGFPTUMYLIVDX-UHFFFAOYSA-N 1-butylindole Chemical group C1=CC=C2N(CCCC)C=CC2=C1 PSGFPTUMYLIVDX-UHFFFAOYSA-N 0.000 description 1
- CLYFXKBQNAQDOJ-UHFFFAOYSA-N 2-butyl-1h-indole Chemical group C1=CC=C2NC(CCCC)=CC2=C1 CLYFXKBQNAQDOJ-UHFFFAOYSA-N 0.000 description 1
- OMOGIBDYNFWHGE-UHFFFAOYSA-N 3-tert-butyl-2-naphthalen-2-yl-1h-indole Chemical compound C1=CC=CC2=CC(C3=C(C4=CC=CC=C4N3)C(C)(C)C)=CC=C21 OMOGIBDYNFWHGE-UHFFFAOYSA-N 0.000 description 1
- ONKNNXATBGUOAT-UHFFFAOYSA-N 3-tert-butyl-2-phenyl-1h-indole Chemical compound N1C2=CC=CC=C2C(C(C)(C)C)=C1C1=CC=CC=C1 ONKNNXATBGUOAT-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- MQRJBSHKWOFOGF-UHFFFAOYSA-L disodium;carbonate;hydrate Chemical compound O.[Na+].[Na+].[O-]C([O-])=O MQRJBSHKWOFOGF-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 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
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a 2-aryl-3-tert-butylindole compound, a preparation method and application thereof, trifluoroacetic acid is used as a catalyst, 1, 3-hexafluoro-2-propanol is used as a solvent, N-tert-butyl protection-2-arylindole compound is used as a substrate, and the tert-butyl migration reaction catalyzed by acid can realize the migration of tert-butyl protecting group from N1 position to C3 position to form a new C-C bond, so that the C2 and C3-position disubstituted indole compound can be effectively synthesized. The reaction condition is mild, the operation is simple and convenient, and the yield is up to 88%.
Description
Technical Field
The invention belongs to the field of indole compounds, and in particular relates to a preparation method and application of a 2-aryl-3-tert-butylindole compound.
Background
Indole is widely used as an important structural skeleton in a plurality of active molecules such as natural products, medicines, pesticides, materials and the like, so that a new method for efficiently synthesizing indole derivatives is attracting attention of a plurality of chemists. The 2, 3-disubstituted indole is an important indole derivative, and has important application prospect in the fields of medicine, material development and the like.
Disclosure of Invention
The invention aims to provide a preparation method of a 2-aryl-3-tertiary butyl indole compound, which uses an N-tertiary butyl-2-aryl indole compound as a substrate and trifluoroacetic acid as a catalyst; by acid-catalyzed t-butyl migration, t-butyl alkylation of the C3 position of indole (i.e., migration of the t-butyl protecting group from the N1 position to the C3 position to form a new C-C bond) can be successfully achieved, and a 2, 3-disubstituted indole compound is constructed. The prepared 2-aryl-3-tertiary butyl indole compounds can be used for preparing bioactive molecules 。
In order to achieve the above purpose, the invention is realized by the following technical scheme:
a preparation method of 2-aryl-3-tert-butylindole compounds, wherein the indole compounds are compounds shown in a formula I,
the preparation method comprises the following steps:
in an inert atmosphere, mixing and reacting the N-tertiary butyl-2-aryl substituted indole compound shown in the formula II in a first organic solvent to obtain a compound I;
in the formula I and the formula II: r is one of hydrogen, methyl, methoxy, ester group or phenyl, and X is one of hydrogen, 4-fluoro, 5-methyl, 5-ester group, 6-methoxy, 6-fluoro, 6-ester group and 6-phenyl.
Preferably, the indole compound is any one of compounds shown in the following formulas I-a-I-m:
preferably, the molar ratio of the N-tertiary butyl-2-aryl substituted indole compound II to the trifluoroacetic acid is 1:0.2.
Preferably, the concentration of the N-tertiary butyl-2-aryl substituted indole compound II in the mixed solution of the N-tertiary butyl-2-aryl substituted indole compound II, trifluoroacetic acid and the first organic solvent is 0.2 mol/L.
Preferably, the first organic solvent is 1, 3-hexafluoro-2-propanol.
Preferably, the reaction time is 3-7 hours and the temperature is room temperature.
Preferably, the reaction time is 3 hours and the temperature is room temperature.
Preferably, the N-tert-butyl-2-aryl-substituted indole compound II is added into a reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol is added, and then trifluoroacetic acid is added dropwise and stirred at room temperature for 3 hours, and K is added 2 CO 3 The reaction was quenched with aqueous solution and extracted with ethyl acetate.
Preferably, the 2-aryl-3-tert-butylindole compound is purified by column chromatography, and the column solvent is petroleum ether; the column packing used was 300-400 mesh silica gel with a specification of 1cm diameter by 15cm height.
Preferably, the 2-aryl-3-tert-butylindole compound is purified by column chromatography, and the column solvent is petroleum ether; the eluent is petroleum ether: dichloromethane.
2-aryl-3-tert-butylindole compound with general formula I
Wherein: r is one of hydrogen, methyl, methoxy, ester group or phenyl, and X is one of hydrogen, 4-fluoro, 5-methyl, 5-ester group, 6-methoxy, 6-fluoro, 6-ester group and 6-phenyl.
Preferably, the indole compound is any one of compounds shown in the following formulas I-a-I-m:
the application of the 2-aryl-3-tert-butylindole compound in preparing bioactive molecules.
Compared with the prior art, the invention has the beneficial effects that:
(1) The 2-aryl-3-tert-butyl substituted indole compound has the advantages of easily available raw materials, simple and convenient operation, and simple and efficient synthesis by the existing method.
(2) According to the invention, N-tertiary butyl-2-aryl substituted indole compounds II with different structures are used as raw materials, trifluoroacetic acid is used as a catalyst, and a series of 2, 3-disubstituted indole compounds can be successfully synthesized through migration of N-tertiary butyl at N1 to C3 positions. The method has the advantages of easy synthesis of raw materials, mild reaction conditions, simple operation and high yield up to 88%.
Detailed Description
Preferred embodiments of the present invention will be described in more detail below in connection with specific examples. The methods are conventional methods unless otherwise specified. The starting materials are commercially available from the public unless otherwise specified. In the column chromatography step of the following examples, the column was packed with 300-400 mesh silica gel having a size of 1cm diameter by 1.5cm diameter by 20cm height.
Example 1
A2-aryl-3-tert-butylindole compound shown in a formula I-a is prepared by the following steps:
compound II-a (0.0623 g,0.25 mmol) was added to the reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol (1.2 ml) was added, followed by dropwise addition of trifluoroacetic acid (3.7. Mu.l, 0.05 mmol) and stirring at room temperature for 3h 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and dried over anhydrous sodium carbonate, filtered, concentrated and further purified by column chromatography under the following conditions: petroleum ether is packed into a column, and the eluent is petroleum ether: dichloromethane (5:1); obtain I-a pale yellow solid (0.0450 g,72% yield).
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.94(d,J＝8.4Hz,1H),7.73(br s,1H),7.48-7.44(m,2H),7.44-7.38(m,3H),7.31(d,J＝8.0Hz,1H),7.20(td,J＝7.2and 1.2Hz,1H),7.14(td,J＝8.0and 1.2Hz,1H),1.39(s,9H)； 13 C NMR(100MHz,CDCl 3 )δ136.6,135.8,133.5,131.0,128.3,127.7,127.5,122.3,121.8,121.6,119.0,110.8,33.3,32.5。
the compound synthesized by structural identification is 2-phenyl-3-tertiary butyl-1H-indole shown as a target compound I-a.
Example 2
A2-aryl-3-tert-butylindole compound shown in the formula I-b is prepared by the following steps:
compound II-l (0.0658 g,0.25 mmol) was added to the reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol (1.2 ml) was added, followed by dropwise addition of trifluoroacetic acid (3.7. Mu.l, 0.05 mmol) and stirring at room temperature for 3h. 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and dried over anhydrous sodium carbonate, filtered, concentrated and further purified by column chromatography under the following conditions: loading petroleum ether into a column, wherein the eluent is petroleum ether; i-l white solid (0.0510 g,77% yield) was obtained.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.91(d,J＝8.0Hz,1H),7.70(br s,1H),7.36-7.28(m,3H),7.22-7.15(m,3H),7.15-7.09(m,1H),2.43(s,3H),1.38(s,9H)； 13 C NMR(100MHz,CDCl 3 ) Delta 138.1,135.8,133.63,133.55,130.9,128.4,127.6,122.3,121.7,121.5,118.9,110.7,33.3,32.5,21.5; the compound synthesized by structural identification is 2-p-tolyl-3-tert-butyl-1H-indole shown as a target compound I-b.
Example 3
A2-aryl-3-tert-butylindole compound shown in the formula I-c is prepared by the following steps:
compound II-c (0.0658 g,0.25 mmol) was added to the reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol (1.2 ml) was added, followed by dropwise addition of trifluoroacetic acid (3.7. Mu.l, 0.05 mmol) and stirring at room temperature for 3h. 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and dried over anhydrous sodium carbonate, filtered, concentrated and further purified by column chromatography under the following conditions: petroleum ether is packed into a column, and the eluent is petroleum ether: dichloromethane (15:1); i-c was obtained as a white solid (0.0520 g,79% yield).
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.92(d,J＝8.0Hz,1H),7.71(br s,1H),7.33-7.21(m,5H),7.21-7.16(m,1H),7.15-7.10(m,1H),2.42(s,3H),1.39(s,9H)； 13 C NMR(100MHz,CDCl 3 ) Delta 137.3,136.5,135.8,133.7,131.7,129.0,128.2,127.6,127.5,122.3,121.6,121.5,119.0,110.7,33.3,32.5,21.5; the compound synthesized by structural identification is 2-m-tolyl-3-tert-butyl-1H-indole shown as a target compound I-b.
Example 4
A2-aryl-3-tert-butylindole compound shown in the formula I-d is prepared by the following steps:
compound II-d (0.0698 g,0.25 mmol) was added to the reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol (1.2 ml) was added, followed by dropwise addition of trifluoroacetic acid (3.7. Mu.l, 0.05 mmol) and stirring at room temperature for 3h. 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and dried over anhydrous sodium carbonate, filtered, concentrated and further purified by column chromatography under the following conditions: petroleum ether is packed into a column, and the eluent is petroleum ether: dichloromethane (5:1); i-d white (0.050 g,72% yield) was obtained.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.91(d,J＝8.0Hz,1H),7.71(br s,1H),7.39-7.33(m,2H),7.30(d,J＝8.0Hz,1H),7.20-7.15(m,1H),7.14-7.09(m,1H),6.94-6.89(m,2H),3.87(s,3H),1.37(s,9H)； 13 CNMR(100MHz,CDCl 3 ) Delta 159.6,135.7,133.3,132.1,128.7,127.6,122.3,121.8,121.5,118.9,113.1,110.7,55.4,33.3,32.5; the compound synthesized by structural identification is 2-p-methoxyphenyl-3-tertiary butyl-1H-indole shown as a target compound I-d.
Example 5
A2-aryl-3-tert-butylindole compound shown in the formula I-e is prepared by the following steps:
compound II-e (0.0762 g,0.25 mmol) was added to the reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol (1.2 ml) was added, followed by dropwise addition of trifluoroacetic acid (3.7. Mu.l, 0.05 mmol) and stirring at room temperature for 3h. 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and dried over anhydrous sodium carbonate, filtered, concentrated and further purified by column chromatography under the following conditions: petroleum ether is packed into a column, and the eluent is petroleum ether: dichloromethane (2:1); i-f white solid (0.0480 g,63% yield) was obtained.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.05(d,J＝8.0Hz,2H),7.93(d,J＝8.0Hz,1H),7.87(br s,1H),7.53(d,J＝8.0Hz,2H),7.33(d,J＝7.2Hz,1H),7.2(t,J＝7.2Hz,1H),7.17-7.10(m,1H),3.96(s,3H),1.37(s,9H)； 13 C NMR(100MHz,CDCl 3 ) Delta 167.0,141.5,136.1,132.2,131.1,129.9,128.9,127.5,122.5,122.4,122.0,119.2,110.9,52.4,33.3,32.5; the compound synthesized by structural identification is 2- (4-methyl formate phenyl) -3-tertiary butyl-1H-indole shown as a target compound I-e.
Example 6
A2-aryl-3-tert-butylindole compound shown in the formula I-f is prepared by the following steps:
compound II-i (0.0749 g,0.25 mmol) was added to the reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol (1.2 ml) was added, followed by dropwise addition of trifluoroacetic acid (3.7. Mu.l, 0.05 mmol) and stirring at room temperature for 3h. 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and dried over anhydrous sodium carbonate, filtered, concentrated and further purified by column chromatography under the following conditions: petroleum ether is packed into a column, and the eluent is petroleum ether: dichloromethane (15:1); i-f white solid (0.0570 g,76% yield) was obtained.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.96(d,J＝8.0Hz,1H),7.94-7.85(m,4H),7.79(br s,1H),7.62-7.52(m,3H),7.34(d,J＝8.0Hz,1H),7.22(t,J＝7.2Hz,1H),7.19-7.13(m,1H),1.41(s,9H)； 13 C NMR(100MHz,CDCl 3 ) Delta 135.9,134.0,133.4,133.0,132.7,129.9,129.1,128.2,127.9,127.6,127.1,126.63,126.60,122.4,122.2,121.7,119.1,110.8,33.4,32.6; the compound synthesized by structural identification is 2- (2-naphthyl) -3-tertiary butyl-1H-indole shown as a target compound I-f.
Example 7
A2-aryl-3-tert-butylindole compound shown in the formula I-g is prepared by the following steps:
compound II-i (0.2674 g,0.75 mmol) was added to the reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol (3.6 ml) was added, followed by dropwise addition of trifluoroacetic acid (11.1. Mu.l, 0.15 mmol) and stirring at room temperature for 3h 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and was then washed with brineDrying sodium carbonate hydrate, filtering, concentrating and purifying by column chromatography, wherein the specific conditions are as follows: petroleum ether is packed into a column, and the eluent is petroleum ether: dichloromethane (6:1); i-g white solid (0.140 g,70% yield) was obtained.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.77(br s,1H),7.48-7.36(m,5H),7.17-7.04(m,2H),6.89-6.78(m,1H),1.34(d,J＝3.2Hz,9H)； 13 C NMR(100MHz,CDCl 3 ) Delta 156.1 (d, j= 244.9 Hz), 138.5 (d, j=11.7 Hz), 136.2,133.6,131.0,128.5,127.7,122.6 (d, j=9.0 Hz), 121.6 (d, j=4.2 Hz), 116.2 (d, j=18.9 Hz), 106.7 (d, j=3.4 Hz), 105.7 (d, j=24.5 Hz), 32.9 (d, j=7.2 Hz), 32.5; the compound synthesized by structural identification is 2-phenyl-3-tertiary butyl-4-fluoro-1H-indole shown as a target compound I-m.
Example 8
A2-aryl-3-tert-butylindole compound shown in the formula I-h is prepared by the following steps:
compound II-h (0.0659 g,0.25 mmol) was added to the reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol (1.2 ml) was added, followed by dropwise addition of trifluoroacetic acid (3.7. Mu.l, 0.05 mmol) and stirring at room temperature for 3h 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and dried over anhydrous sodium carbonate, filtered, concentrated and further purified by column chromatography under the following conditions: petroleum ether is packed into a column, and the eluent is petroleum ether: dichloromethane (5:1); i-h white solid (0.0470 g,72% yield) was obtained.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.70(s,1H),7.63(br s,1H),7.47-7.43(m,2H),7.42-7.36(m,3H),7.20(d,J＝8.4Hz,1H),7.02(d,J＝8.4Hz,1H),2.51(s,3H),1.38(s,9H)； 13 C NMR(100MHz,CDCl 3 ) Delta 136.8,134.2,133.7,131.0,128.2,128.1,127.8,127.6,123.1,122.0,121.4,110.4,33.3,32.5,22.0; the compound synthesized by structural identification is 2-percent of target compound I-hphenyl-3-tert-butyl-5-methyl-1H-indole.
Example 9
A2-aryl-3-tert-butylindole compound shown in the formula I-I is prepared by the following steps:
compound II-i (0.0769 g,0.25 mmol) was added to the reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol (1.2 ml) was added, followed by dropwise addition of trifluoroacetic acid (3.7. Mu.l, 0.05 mmol) and stirring at room temperature for 3h. 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and dried over anhydrous sodium carbonate, filtered, concentrated and further purified by column chromatography under the following conditions: petroleum ether is packed into a column, and the eluent is petroleum ether: dichloromethane (2:1); I-I white solid (0.0650 g,85% yield) was obtained.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.68(s,1H),7.95(br s,1H),7.89(d,J＝8.4Hz,1H),7.46-7.37(m,5H),7.30(d,J＝8.8Hz,1H),3.95(s,3H),1.38(s,9H)； 13 C NMR(100MHz,CDCl 3 )δ168.5,138.4,135.8,134.7,130.9,128.6,127.8,127.2,125.3,123.22,123.16,121.0,110.3,52.0,33.3,32.6.
the compound synthesized by structural identification is 2-phenyl-3-tertiary butyl-1H-indole-5-methyl formate shown as a target compound I-I.
Example 10
A2-aryl-3-tert-butylindole compound shown in the formula I-j is prepared by the following steps:
compound II-j ((0.0668 g,0.25 mmol) was added to the reaction vessel, first organic solvent 1, 3-hexafluoro-2-propanol (1.2 ml) was added, followed by dropwise addition of trifluoroacetic acid (3.7. Mu.l, 0.05 mmol) and stirring at room temperature for 3h. 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and dried over anhydrous sodium carbonate, filtered, concentrated and further purified by column chromatography under the following conditions: petroleum ether is packed into a column, and the eluent is petroleum ether: dichloromethane (10:1); i-j white solid (0.0510 g,76% yield) was obtained.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.81(dd,J＝8.8and5.2Hz,1H),7.71(br s,1H),7.47-7.38(m,5H),6.98(dd,J＝9.6,2.4Hz,1H),6.89(td,J＝9.2,2.8Hz,1H),1.35(d,J＝3.2Hz,9H)； 13 C NMR(100MHz,CDCl 3 ) δ 159.6 (d, j=236.0 Hz), 136.2,135.8 (d, j=12.0 Hz), 133.8 (d, j=4.0 Hz), 131.0,128.4,127.8,124.1,123.0 (d, j=9.0 Hz), 121.8,107.6 (d, j=23.0 Hz), 96.9 (d, j=25.0 Hz), 33.2,32.5; the compound synthesized by structural identification is 2-phenyl-3-tertiary butyl-7-fluoro-1H-indole shown as a target compound I-j.
Example 11
A2-aryl-3-tert-butylindole compound shown in the formula I-k is prepared by the following steps:
compound II-k (0.0768 g,0.25 mmol) was added to the reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol (1.2 ml) was added, followed by dropwise addition of trifluoroacetic acid (3.7. Mu.l, 0.05 mmol) and stirring at room temperature for 3h. 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and dried over anhydrous sodium carbonate, filtered, concentrated and further purified by column chromatography under the following conditions: petroleum ether is packed into a column, and the eluent is petroleum ether: diethyl ether (7:1); i-k white solid (0.0640 g,83% yield) was obtained.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.14-8.02(m,2H),7.92(d,J＝8.4Hz,1H),7.79(dd,J＝8.8and 2.0Hz,1H),7.47-7.37(m,5H),3.92(s,3H),1.36(s,9H)； 13 C NMR(100MHz,CDCl 3 )δ168.3,137.1,135.9,135.1,131.2,130.8,128.6,127.8,123.1,122.5,121.8,120.0,113.1,52.1,33.3,32.5; the compound synthesized by structural identification is 2-phenyl-3-tertiary butyl-1H-indole-7-methyl formate shown as a target compound I-k.
Example 12
A2-aryl-3-tert-butylindole compound shown in the formula I-l is prepared by the following steps:
compound II-l (0.0698 g,0.25 mmol) was added to the reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol (1.2 ml) was added, followed by dropwise addition of trifluoroacetic acid (3.7. Mu.l, 0.05 mmol) and stirring at room temperature for 3h. 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and dried over anhydrous sodium carbonate, filtered, concentrated and further purified by column chromatography under the following conditions: petroleum ether is packed into a column, and the eluent is petroleum ether: dichloromethane (5:1); i-l white solid (0.0520 g,74% yield) was obtained.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.78(d,J＝9.6Hz,1H),7.63(br s,1H),7.47-7.42(m,2H),7.41-7.35(m,3H),6.85-6.75(m,2H),3.85(s,3H),1.35(s,9H)； 13 C NMR(100MHz,CDCl 3 ) Delta 156.0,136.7,136.6,132.3,131.2,128.2,127.7,122.9,121.9,121.7,108.8,94.2,55.8,33.2,32.5; the compound synthesized by structural identification is 2-phenyl-3-tertiary butyl-7-methoxy-1H-indole shown as a target compound I-l.
Example 13
A2-aryl-3-tert-butylindole compound shown in the formula I-m is prepared by the following steps:
compound II-m (0.0814 g,0.25 mmol) was charged into a reaction vessel, and a first organic solvent 1, 3-hexafluoro-2-propanol (1.2 ml) was added, followed by the following stepsTrifluoroacetic acid (3.7. Mu.l, 0.05 mmol) was added dropwise and stirred at room temperature for 3h 1M K was added 2 CO 3 Quenching the reaction with water solution and extracting with ethyl acetate; the organic phase was washed with saturated brine and dried over anhydrous sodium carbonate, filtered, concentrated and further purified by column chromatography under the following conditions: petroleum ether is packed into a column, and the eluent is petroleum ether: dichloromethane (5:1); i-m white solid (0.0680 g,84% yield) was obtained.
The structure validation results are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.97(d,J＝8.0Hz,1H),7.81(br s,1H),7.69-7.64(m,2H),7.52(d,J＝1.6Hz,1H),7.50-7.44(m,4H),7.44-7.37(m,5H),7.33(tt,J＝7.6and 1.2Hz,1H),1.40(s,9H)； 13 CNMR(100MHz,CDCl 3 ) Delta 142.4,136.43,136.37,135.2,134.3,131.0,128.8,128.4,127.7,127.5,126.9,126.7,122.5,121.9,118.9,109.2,33.3,32.5; the compound synthesized by structural identification is 2-phenyl-3-tertiary butyl-7-phenyl-1H-indole shown as a target compound I-m.
Claims (10)
1. A preparation method of 2-aryl-3-tert-butylindole compounds is characterized in that the indole compounds are compounds shown in a formula I,
the preparation method comprises the following steps:
in an inert atmosphere, mixing and reacting the N-tertiary butyl-2-aryl substituted indole compound shown in the formula II in a first organic solvent to obtain a compound I;
in the formula I and the formula II: r is one of hydrogen, methyl, methoxy, ester group or phenyl, and X is one of hydrogen, 4-fluoro, 5-methyl, 5-ester group, 6-methoxy, 6-fluoro, 6-ester group and 6-phenyl.
2. The method for preparing a 2-aryl-3-tert-butylindole compound according to claim 1, wherein the indole compound is any one of compounds represented by the following formulas i-a to i-m:
3. the method for preparing 2-aryl-3-tert-butylindole compound according to claim 1 or 2, wherein the molar ratio of N-tert-butyl-2-aryl substituted indole compound II to trifluoroacetic acid is 1:0.2.
4. The process for producing a 2-aryl-3-t-butylindole compound according to claim 1 or 2, wherein the concentration of the N-t-butyl-2-aryl-substituted indole compound II in the mixed solution of the N-t-butyl-2-aryl-substituted indole compound II, trifluoroacetic acid and the first organic solvent is 0.2 mol/l.
5. The method for producing a 2-aryl-3-tert-butylindole compound according to claim 1 or 2, wherein the first organic solvent is 1, 3-hexafluoro-2-propanol.
6. The process for producing a 2-aryl-3-t-butylindole compound according to claim 1 or 2, wherein the reaction time is 3 hours and the temperature is room temperature.
7. The process for preparing a 2-aryl-3-tert-butylindole compound according to claim 1 or 2, wherein in the preparation, N-tert-butyl-2-aryl-substituted indole compound II is added into a reaction vessel, a first organic solvent 1, 3-hexafluoro-2-propanol is added, and then trifluoroacetic acid is added dropwise and stirred at room temperature for 3 hours, and K is added 2 CO 3 The reaction is quenched by the water solution,and extracted with ethyl acetate.
8. A2-aryl-3-tert-butylindole compound is characterized in that the general formula of the indole compound is I
Wherein: r is one of hydrogen, methyl, methoxy, ester group or phenyl, and X is one of hydrogen, 4-fluoro, 5-methyl, 5-ester group, 6-methoxy, 6-fluoro, 6-ester group and 6-phenyl.
9. The 2-aryl-3-tert-butylindole compound according to claim 1, wherein the indole compound is any one of the following compounds represented by formulas i-a to i-m:
10. use of a 2-aryl-3-tert-butylindole compound according to any one of claims 1 to 9 for the preparation of a bioactive molecule.
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| WO2013159229A1 (en) * | 2012-04-24 | 2013-10-31 | Dalhousie University | Silanyloxyaryl phosphine ligand and uses thereof in c-n cross-coupling |
| CN113683551A (en) * | 2021-09-09 | 2021-11-23 | 常州大学 | N-tert-butyl-2-phenylindole derivative, preparation method and application |
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| WO2013159229A1 (en) * | 2012-04-24 | 2013-10-31 | Dalhousie University | Silanyloxyaryl phosphine ligand and uses thereof in c-n cross-coupling |
| CN113683551A (en) * | 2021-09-09 | 2021-11-23 | 常州大学 | N-tert-butyl-2-phenylindole derivative, preparation method and application |
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| CHEMICAL ABSTRACT SERVICE: "RN：2558437-02-6、2552338-48-2、2548251-88-1、2539233-68-4、2533419-92-8、2509965-69-7、2441613-70-1", CA网络版STN REGISTRY数据库, 14 December 2020 (2020-12-14) * |
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