CN111484440B - Indole triarylmethane derivative based on phenylboronic acid and synthetic method thereof - Google Patents
Indole triarylmethane derivative based on phenylboronic acid and synthetic method thereof Download PDFInfo
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- CN111484440B CN111484440B CN201910087761.8A CN201910087761A CN111484440B CN 111484440 B CN111484440 B CN 111484440B CN 201910087761 A CN201910087761 A CN 201910087761A CN 111484440 B CN111484440 B CN 111484440B
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Abstract
The invention discloses a method for synthesizing an indole triarylmethane derivative based on phenylboronic acid, which is synthesized by using ferric trichloride as a catalyst and performing one-pot reaction on various substituted salicylaldehyde, phenylboronic acid and indole. The three different aryls are introduced from cheap and easily available substituted salicylaldehyde, phenylboronic acid and indole in one step under the condition of no alkali/ligand, the reaction has high chemical selectivity, the reaction method is simple and convenient to operate, the reaction time is short, the catalyst is cheap and easy to obtain, the production cost is low, the pollution is less, the post-treatment is simple, and the reaction has good yield.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an indole triarylmethane derivative based on phenylboronic acid and a synthesis method thereof.
Background
The indolyl-substituted triarylmethane derivative is widely used in reductase inhibitor, antiviral medicine, anticancer medicine, dye material, bioactive alkaloid and other natural products, and has important use in medicinal chemistry and material science. The methods used so far for the synthesis of indole triarylmethane derivatives are mainly: diphenyl carbinol (ester, ether, imine, and the like) directly reacts with aromatic hydrocarbon through a Friedel-crafts alkylation method, the synthetic method is generally easy to react on the aromatic hydrocarbon containing electron-donating groups, a reaction substrate has certain limitation, and an isomer byproduct is easy to generate; the other synthetic method is synthesized by cross coupling reaction or carbon-hydrogen functionalization reaction catalyzed by transition metal; yet another method is to synthesize by 1, 6-addition arylation of p-benzoquinone derivatives. There are some obvious disadvantages in the above synthetic methods, such as: limited substrate range, poor regioselectivity, expensive transition metals often used in the reaction, multi-step reactions and harsh reaction conditions.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a synthesis method of an indole triarylmethane derivative based on phenylboronic acid, which is a one-pot reaction and is prepared from cheap and environment-friendly FeCl3As a catalyst, synthesizing and preparing the indole triarylmethane derivative.
The invention also aims to provide the indole triarylmethane derivative obtained by the synthesis method.
The purpose of the invention is realized by the following technical scheme.
A synthetic method of indole triarylmethane derivative based on phenylboronic acid comprises the following steps:
mixing a first reactant, a second reactant, piperidine, a catalyst and a solvent, reacting for 15-20 min at 40-120 ℃ under stirring, adding a third reactant, reacting for 20-80 min at 40-120 ℃ under stirring, cooling to room temperature of 20-25 ℃ after the reaction is finished, adding ethyl acetate, and washing to obtain an organic phase; drying the organic phase, evaporating the solvent under reduced pressure to obtain a residue, separating the residue by column chromatography, evaporating the solvent again, and drying to obtain the indole triarylmethane derivative, wherein the catalyst is FeCl3The ratio of the first reactant, the second reactant, the third reactant, the catalyst, and the piperidine, by mass, is 1: (1-1.5): (1-1.5): (0.5-1): (1-1.2).
The first reactant is
The second reactant is
The third reactant is
In the technical scheme, the unit of the quantity part of the substance is mmol, and the unit of the volume part is mL.
In the above technical solution, the ratio of the parts by weight of the first reactant, the parts by volume of the solvent, and the parts by volume of the ethyl acetate is 1: (1-2): 50.
in the above technical solution, the solvent is one or more of toluene, chlorobenzene, 1, 4-dioxane, acetonitrile, ethanol, water, dichloroethane, and dimethylformamide, and is used to provide a uniformly dispersed atmosphere for the first reactant, the second reactant, the piperidine, and the third reactant.
In the technical scheme, a mixed solution of n-hexane and ethyl acetate is used as an eluent for column chromatography separation, and the ratio of the n-hexane to the ethyl acetate is 6:1 in parts by volume.
In the technical scheme, the washing is sequentially washed by water and saturated saline solution.
In the technical scheme, after the third reactant is added, the stirring reaction is preferably carried out at 100 ℃ for 20-80 min.
In the technical scheme, the reaction time after the third reactant is added is determined by adopting thin layer chromatography detection.
In the above technical solution, the operation steps of drying the organic phase are as follows: to the organic phase was added anhydrous sodium sulfate for drying, and the anhydrous sodium sulfate was filtered.
The indole triarylmethane derivative obtained by the synthesis method.
The synthesis method has the advantages of simple operation, short reaction time, cheap and easily-obtained catalyst, low production cost, less pollution, simple post-treatment and high reaction yield.
Detailed Description
In the specific implementation mode of the invention, the reagents and the medicines involved in the synthesis method are purchased from Tianjin reagent six factories, the purity of the medicines is analytically pure, and the reagents and the medicines are directly used without any pretreatment.
The synthesis method of the invention continuously stirs in the whole process, and the model of an electromagnetic heating stirrer used for stirring is NUOVAII (Temaran, USA); the rotary evaporator was model RE-2000A (Otsuwa instruments liability Co., Ltd., Otsu). Nuclear magnetic resonance instrument model: bruker AV-400spectrometer, 400 MHz. In the following examples, the degree of progress of the reaction was checked by Thin Layer Chromatography (TLC) at the time of heating reflux reaction. In thin layer chromatography, a G254 silica gel plate with a size of 15mm × 50mm, a ZF-I type three-purpose ultraviolet analyzer (Shanghai Ching), and used medicines purchased from Tianjin reagent six factories are analytically pure and all are directly used without any pretreatment. When the TLC detection shows that the first reactant of the raw material disappears and only the target compound is in the spot, the synthesis method of the invention is marked to be finished, and the next separation operation can be continued.
In the following examples, the room temperature is 20 to 25 ℃. When column chromatography is used for separation, the polarity of the developing solvent is as follows: n-hexane/ethyl acetate 6:1 (parts by volume).
The organic phase was dried over anhydrous sodium sulfate and filtered: the organic phase was dried by adding anhydrous sodium sulfate, and the anhydrous sodium sulfate was filtered.
In a particular embodiment of the invention, the amount of substance is in mmol and the volume is in ml.
In the following examples, the solvent was distilled off twice under reduced pressure, and the first distillation under reduced pressure was conducted so as to remove as much of the solvent as possible (possibly with a residue), and the remaining solvent was distilled off in the second distillation (the ratio of the volume of the solvent distilled off in the first distillation to the volume of the solvent distilled off in the second distillation did not affect the effect of obtaining the target compound in the following examples).
The technical scheme of the invention is further explained by combining specific examples.
Example 1
A method for synthesizing an indole triarylmethane derivative ((3-indolyl) (2-hydroxy-5-chlorophenyl) (phenyl) methane) based on phenylboronic acid, comprising the steps of:
1.0mmol (0.156g) of 5-chlorosalicylaldehyde, 1.0mmol (0.122g) of phenylboronic acid, 1.2mmol (0.102g) of piperidine and 0.5mmol (0.081g) of FeCl are sequentially added3(catalyst) and 2ml solvent chlorobenzene were added to a 10ml dry round bottom flask and heated at 100 ℃ for 15 minutes. Then adding 1.2mmol (0.140g) of indole, continuing heating reflux reaction at 100 ℃, monitoring the reaction by TLC, cooling to room temperature after the reaction is completed, adding 50ml of ethyl acetate into the reaction system, washing with 30ml of water and saturated salt water in sequence, drying and filtering an organic phase by anhydrous sodium sulfate, evaporating under reduced pressure to remove a large amount of solvent, separating the residue by column chromatography, adopting a mixed solution of normal hexane and ethyl acetate as an eluent, evaporating to remove the solvent again until the solvent is completely volatilized, drying to obtain a target compound with the reaction yield of 82%,1H NMR(400MHz,DMSO-d6):δ＝5.92(s,1H,CH),6.67(s,1H,ArH),6.88(t,J＝7.2Hz,2H,ArH),7.06-7.10(m,3H,ArH),7.21(t,J＝8.0Hz,3H,ArH),7.29(d,J＝7.2Hz,2H,ArH),7.38(d,J＝8.0Hz,2H,ArH),9.79(s,1H,OH),10.90(s,1H,NH).13C NMR(100MHz,DMSO-d6):δ＝41.9,112.8,117.8,118.2,119.6,119.9,122.3,123.3,125.4,127.2,127.6,128.0,129.3,129.7,130.5,133.8,137.9,144.5,154.8.
example 2
A method for synthesizing an indole triarylmethane derivative ((3-indolyl) (2-hydroxy-3, 5-dichlorophenyl) (phenyl) methyl) based on phenylboronic acid, comprising the steps of:
1.0mmol (0.190g) of 3, 5-dichlorosalicylaldehyde, 1.0mmol (0.122g) of phenylboronic acid, 1.2mmol (0.102g) of piperidine and 0.5mmol (0.081g) of FeCl are sequentially added3(catalyst) and 2ml solvent chlorobenzene were added to a 10ml dry round bottom flask and heated at 100 ℃ for 15 minutes. Then adding 1.2mmol (0.140g) of indole, continuing heating reflux reaction at 100 ℃, monitoring the reaction by TLC, cooling to room temperature after the reaction is completed, adding 50ml of ethyl acetate into the reaction system, washing with 30ml of water and saturated salt water in sequence, drying and filtering an organic phase by anhydrous sodium sulfate, evaporating under reduced pressure to remove a large amount of solvent, separating the residue by column chromatography, adopting a mixed solution of normal hexane and ethyl acetate as an eluent, evaporating to remove the solvent again until the solvent is completely volatilized, drying to obtain a target compound, wherein the reaction yield is 91%,1H NMR(400MHz,DMSO-d6):δ＝6.05(s,1H,CH),6.69(s,1H,ArH),6.82(s,1H,ArH),6.91(t,J＝6.8Hz,1H,ArH),7.06-7.14(m,2H,ArH),7.21-7.24(m,3H,ArH),7.31(t,J＝7.6Hz,2H,ArH),7.38-7.41(m,2H,ArH),9.70(s,1H,OH),10.97(s,1H,NH).13C NMR(100MHz,DMSO-d6):δ＝41.5,111.6,116.4,118.6,121.3,121.8,123.0,124.5,126.3,126.7,127.7,128.3,128.5,135.4,136.7,142.7,149.4.
example 3
A method for synthesizing an indole triarylmethane derivative ((3-indolyl) (2-hydroxy-3, 5-dibromophenyl) (phenyl) methane) based on phenylboronic acid, comprising the following steps:
1.0mmol (0.190g) of 3, 5-dibromo salicylaldehyde, 1.0mmol (0.122g) of phenylboronic acid, 1.2mmol (0.102g) of piperidine and 0.5mmol (0.081g) of FeCl are sequentially added3(catalyst) and 2ml solvent chlorobenzene were added to a 10ml dry round bottom flask and heated at 100 ℃ for 15 minutes. Then adding 1.2mmol (0.140g) indole, heating at 100 deg.C for reflux reaction, monitoring reaction by TLC, cooling to room temperature after reaction is completedAdding 50ml ethyl acetate into a reaction system, washing with 30ml water and saturated salt water in sequence, drying and filtering an organic phase by anhydrous sodium sulfate, evaporating under reduced pressure to remove a large amount of solvent, separating the residue by column chromatography, evaporating again to remove the solvent by using a mixed solution of normal hexane and ethyl acetate as an eluent until the solvent is completely volatilized, drying to obtain the target compound with the reaction yield of 93 percent,1H NMR(400MHz,DMSO-d6):δ＝6.11(s,1H,CH),6.71(s,1H,ArH),6.92(t,J＝7.6Hz,1H,ArH),7.02(s,1H,ArH),7.10(t,J＝7.2Hz,1H,ArH),7.17(d,J＝8.0Hz,1H,ArH)7.21-7.24(m,3H,ArH),7.32(t,J＝8.0Hz,2H,ArH),7.43(d,J＝8.0Hz,1H,ArH),7.63(s,1H,ArH),9.58(s,1H,OH),10.99(s,1H,NH).13C NMR(100MHz,DMSO-d6):δ＝42.9,112.3,112.9,113.8,117.7,119.8,119.9,122.5,125.7,127.5,129.5,129.8,132.4,133.5,137.2,137.9,143.9,152.1.
the accurate attribution of the hydrogen chemical shift results and the signal attribution of carbon atoms of carbon spectra of pure compounds obtained in each example in nuclear magnetic resonance hydrogen spectra are also attached to the operation steps of each example, and the synthesized products are proved to be the indole triarylmethane derivatives.
Compared with the content disclosed in the prior art, the synthetic method disclosed by the invention has the advantages and characteristics that: the synthesis method has the advantages of simple synthesis steps, short reaction time, high yield, cheap and easily-obtained reaction raw materials and used catalysts, and wide application range of the substrate. In addition, the synthesis method of the invention has simple post-reaction treatment: after the reaction is finished, the product is obtained by simple filtration and column chromatography separation.
The invention has been described in an illustrative manner, and it is to be understood that any simple variations, modifications or other equivalent changes which can be made by one skilled in the art without departing from the spirit of the invention fall within the scope of the invention.
Claims (6)
1. A synthetic method of indole triarylmethane derivative based on phenylboronic acid is characterized by comprising the following steps:
will be firstMixing a first reactant, a second reactant, piperidine, a catalyst and a solvent, reacting for 15-20 min under the condition of stirring at 100 ℃, adding a third reactant, reacting for 20-80 min under the condition of stirring at 100 ℃, cooling to room temperature of 20-25 ℃ after the reaction is finished, adding ethyl acetate, and washing to obtain an organic phase; drying the organic phase, evaporating the solvent under reduced pressure to obtain a residue, separating the residue by column chromatography, evaporating the solvent again, and drying to obtain the indole triarylmethane derivative, wherein the catalyst is FeCl3The ratio of the first reactant, the second reactant, the piperidine, the catalyst, and the third reactant is 1: (1-1.5): (1-1.5): (0.5-1): (1-1.2);
the first reactant is
The second reactant is
The third reactant is
The solvent is chlorobenzene, which is used to provide a uniformly dispersed atmosphere for the first, second, piperidine, and third reactants.
2. The synthesis method according to claim 1, wherein the ratio of the parts by weight of the first reactant, the parts by volume of the solvent, and the parts by volume of the ethyl acetate is 1: (1-2): 50, the unit of parts by weight of the substance is mmol, and the unit of parts by volume is mL.
3. The synthesis method according to claim 2, characterized in that a mixed solution of n-hexane and ethyl acetate is used as an eluent for column chromatographic separation, and the ratio of n-hexane to ethyl acetate is 6:1 in parts by volume.
4. The synthesis method according to claim 3, wherein the washing is carried out by sequentially washing with water and saturated brine.
5. The method of claim 4, wherein the time of the reaction after the addition of the third reactant is determined by thin layer chromatography.
6. The synthesis process according to claim 5, characterized in that the drying of the organic phase comprises the following operative steps: to the organic phase was added anhydrous sodium sulfate for drying, and the anhydrous sodium sulfate was filtered.
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Citations (2)
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| CN101037375A (en) * | 2007-04-28 | 2007-09-19 | 郑州大学 | Method for synthesizing triarylmethane and derivatives |
| JP2009215223A (en) * | 2008-03-11 | 2009-09-24 | Nippon Steel Chem Co Ltd | Method for producing indole derivative |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101037375A (en) * | 2007-04-28 | 2007-09-19 | 郑州大学 | Method for synthesizing triarylmethane and derivatives |
| JP2009215223A (en) * | 2008-03-11 | 2009-09-24 | Nippon Steel Chem Co Ltd | Method for producing indole derivative |
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| CAN-catalyzed microwave promoted reaction of indole with Betti bases under solvent-free condition and evaluation of antibacterial activity of the products;Choitanya Dev Peg et al.;《Synthetic Communications》;20171231;第47卷(第21期);第2007-2014页 * |
| Facile synthesis of nonsymmetrical heteroarylsubstituted triarylmethanes via the FeCl3•6H2O catalyzed two-step Friedel–Crafts-type reaction;J. Jaratjaroonphong et al.;《Org. Biomol. Chem》;20161231;第8493-8502页 * |
| FeCl3 as Lewis acid catalyzed one-pot three-component aza-Friedel-Crafts reactions of indoles, aldehydes, and tertiary aromatic amines;Lei Wang et al.;《Tetrahedron》;20110412;第67卷;第3420-3426页 * |
| FeCl3-Catalyzed 1,2-Addition Reactions of Aryl Aldehydes with Arylboronic Acids;Jin-Heng Li et al.;《Organic Letters》;20091231;第11卷(第2期);第453-456页 * |
| Multifold C−C Coupling and Unorthodox Cyclization Catalysis for Selective Synthesis of Indolotriarylmethanes, Indolocarbazoles, and Their Analogues: A Control Experiment Study;Dilip K. Maiti et al.;《J. Org. Chem.》;20161215;第82卷;第688-700页 * |
| Synthesis of Nitroalkenes Involving a Cooperative Catalytic Action of Iron(III) and Piperidine: A One-Pot Synthetic Strategy to 3-Alkylindoles, 2H-Chromenes and N-Arylpyrrole;Swapnadeep Jalal et al.;《Eur. J. Org. Chem.》;20130617;第4823-4828页 * |
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