CN114478541B - Method for synthesizing imidazo [4,5-b ] indole-2-thione derivative in metal-free catalytic system - Google Patents

Method for synthesizing imidazo [4,5-b ] indole-2-thione derivative in metal-free catalytic system Download PDF

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CN114478541B
CN114478541B CN202210144497.9A CN202210144497A CN114478541B CN 114478541 B CN114478541 B CN 114478541B CN 202210144497 A CN202210144497 A CN 202210144497A CN 114478541 B CN114478541 B CN 114478541B
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indole
imidazo
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CN114478541A (en
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徐瑶
张小祥
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Nanjing Forestry University
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The application discloses a method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system, which comprises the steps of adding 2- (ethynyl) nitrobenzene compounds, thiourea compounds, triphenylphosphine and inorganic base into a certain amount of organic solvent, heating and stirring, and performing rotary evaporation chromatography for separation and purification. The application adopts the simple and easily obtained 2- (ethynyl) nitrobenzene and thiourea derivatives as raw materials, and does not need a metal catalyst in the reaction. The method is simple to operate, mild in reaction conditions, high in yield and good in functional group compatibility, and the prepared imidazo [4,5-b ] indole-2-thioketone compound is complex in structure, can provide convenience for further modification of molecular structures, and has important application value in the research direction of anti-hypoxia active compounds of pharmaceutical chemistry.

Description

Method for synthesizing imidazo [4,5-b ] indole-2-thione derivative in metal-free catalytic system
Technical Field
The application belongs to the field of chemical synthesis, and in particular relates to a method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system.
Background
2, 3-diaminoindole is a very important class of nitrogen-containing heterocyclic compounds which are widely applied to the fields of medicines, pesticides, materials and the like because of good biological activity and a plurality of active reaction sites in the structure, and the compounds often have anti-inflammatory, antibacterial, antiviral, anticancer and other pharmacological activities, for example [1,2,3] triazolo [4,5-b ] indole has antiviral and antibacterial properties (hetercycl.Commun., 1999,5,473-480); the 5H-pyrazino [2,3-b ] indoles are useful as highly selective agonists, antagonists or inverse agonists of GABA brain receptors (org. Biomol. Chem.,2018,16,38-42).
Thiourea and its derivatives have important applications in agriculture, medicine, industry and analytical chemistry in general, for example, they can be used as plant growth regulators to promote germination of corn seeds remarkably (university of Huazhong university, 1999,32,1-5); has better bactericidal activity (chemical reagent, 2005,27,223-224) on cotton fusarium wilt, rice sheath blight and the like; can be used as anti-AIDS drug (J.Med. Chem.,1991,34,3187-3197); can be applied to metal preservative and antioxidant; can be used as toner and developer in photographic materials; can be used as electroless plating resistant agent, brightening agent and surfactant in electroplating; can be used as RNA transcriptases, nucleotide reductase inhibitors and human blood isotope labels.
At present, various methods have been reported for synthesizing 2, 3-diaminoindole, such as copper-catalyzed ring-opening amination of 2-imino-3-indole diazonium compound with benzisoxazole to obtain intermediate product, and reduction by palladium carbon hydrogenation to obtain 2, 3-diaminoindole (CN 111393351 A,2020.07.10); the PhI (OAc) 2 oxidizes N, N-dibenzyloxy urea to generate dinitrogen-oxyallyl cation, and then the dinitrogen-oxyallyl cation and indole undergo [3+2] cycloaddition reaction to obtain imidazo indoline (org.Lett., 2016,18,476-479) and the like.
However, only 2 methods have been reported to synthesize 2, 3-diaminoindole molecules containing thiourea structure, which is called imidazo [4,5-b ] indole-2-thione, in which the first method is a cyclization method of 2-aminoindolinone with potassium thiocyanate under acidic conditions (russ. J. Org. Chem.,1998,34,570-582); the second method is a one-pot three-step synthesis of palladium-catalyzed 2-alkynylarylazides and thioureas previously reported by the inventors (org. Chem. Front.,2020,7,3480-3485). Both of these synthetic methods have limitations such as difficulty in preparing raw materials, use of noble metal catalysts, uneconomical multi-step reactions, inconvenience in operation of purifying the product, low yield of the product, and the like. In addition, the imidazo [4,5-b ] indole-2-thione derivatives have been studied by animal experiments to have remarkable anti-hypoxia activity (pharm.chem.j., 1998,32,59-63).
Disclosure of Invention
This section is intended to outline some aspects of embodiments of the application and to briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section as well as in the description of the application and in the title of the application, which may not be used to limit the scope of the application.
The present application has been made in view of the above and/or problems occurring in the prior art.
It is therefore an object of the present application to overcome the disadvantages of the prior art and to provide a method for the synthesis of imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system.
In order to solve the technical problems, the application provides the following technical scheme: a method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system, comprising,
adding 2- (ethynyl) nitrobenzene compounds, thiourea compounds, triphenylphosphine and inorganic base into an organic solvent, heating and stirring, and performing rotary evaporation chromatography to separate and purify to obtain a target product imidazo [4,5-b ] indole-2-thione;
the inorganic base is any one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate and cesium carbonate;
the organic solvent is any one of acetonitrile, 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide;
the imidazo [4,5-b ] indole-2-thioketone compound of the target product is shown in a formula (I):
the 2- (ethynyl) nitrobenzene compound is shown in a formula (II):
the thiourea compound is shown in a formula (III):
r in the formulae (I) to (III) 1 、R 2 、R 3 Are each independently a group, wherein R 1 Including hydrogen, methoxy, alkyl, halogen; r is R 2 Including methyl, ethyl, n-butyl, phenyl; r is R 3 Including halogen substituted phenyl, alkyl substituted phenyl, thiophene, alkyl.
As a preferred embodiment of the method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to the present application, wherein: the heating and stirring are carried out by heating to 80-90 ℃ and stirring at 400-500 rpm for 5-10 h.
As a preferred embodiment of the method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to the present application, wherein: the rotary evaporation chromatography is used for separation and purification, wherein 100-200 mesh column chromatography silica gel is adopted for separation, and the developing agent is petroleum ether, ethyl acetate and ethyl acetate: the volume ratio of petroleum ether is 1: 40-1: 3.
as a preferred embodiment of the method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to the present application, wherein: the volume mole ratio of the organic solvent to the 2- (ethynyl) nitrobenzene compound is as follows in mL: the mol ratio is 1:0.1.
As a preferred embodiment of the method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to the present application, wherein: the molar ratio of the 2- (ethynyl) nitrobenzene compounds to the thiourea compounds is 1-3:3.
As a preferred embodiment of the method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to the present application, wherein: the molar ratio of the 2- (ethynyl) nitrobenzene compounds to the thiourea compounds is 1:3.
As a preferred embodiment of the method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to the present application, wherein: the molar ratio of the 2- (ethynyl) nitrobenzene compounds to the triphenylphosphine is 1-3:5.
As a preferred embodiment of the method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to the present application, wherein: the molar ratio of the 2- (ethynyl) nitrobenzene compounds to the triphenylphosphine is 1:5.
As a preferred embodiment of the method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to the present application, wherein: the molar ratio of the 2- (ethynyl) nitrobenzene compounds to the potassium carbonate is 1-3:2.
As a preferred embodiment of the method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to the present application, wherein: the molar ratio of the 2- (ethynyl) nitrobenzene compounds to the potassium carbonate is 1:2.
The application has the beneficial effects that:
(1) The application provides a novel method for synthesizing imidazo [4,5-b ] indole-2-thioketone derivatives by using 2- (ethynyl) nitrobenzene in a metal-free catalytic system, which takes simple and easily obtained 2- (ethynyl) nitrobenzene and thiourea derivatives as raw materials, does not need a metal catalyst in the reaction, and has the advantages of simple operation, mild reaction condition, good functional group compatibility, high product yield, environmental protection and the like.
(2) The imidazo [4,5-b ] indole-2-thioketone compound provided by the application has a complex structure, can provide convenience for further molecular structure transformation, and has important application value in the research direction of the medicinal chemical anti-hypoxia active compound.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, 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 application, 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 hydrogen nuclear magnetic resonance spectrum of 1aa prepared in example 1 of the present application;
FIG. 2 is a nuclear magnetic resonance spectrum of 1aa prepared in example 1 of the present application;
FIG. 3 is a hydrogen nuclear magnetic resonance spectrum of 1ba prepared in example 2 of the present application;
FIG. 4 is a hydrogen nuclear magnetic resonance spectrum of 1da prepared in example 4 of the present application;
FIG. 5 is a hydrogen nuclear magnetic resonance spectrum of 1fa prepared in example 6 of the present application;
FIG. 6 is a hydrogen nuclear magnetic resonance spectrum of 1ha prepared in example 8 of the present application;
FIG. 7 is a hydrogen nuclear magnetic resonance spectrum of 1ja prepared in example 10 of the present application;
FIG. 8 is a nuclear magnetic resonance hydrogen spectrum of 1ab prepared in example 11 of the present application.
Detailed Description
In order that the above-recited objects, features and advantages of the present application will become more apparent, a more particular description of the application 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 application, but the present application may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present application 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 application. 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 raw materials in the application are all common commercial products.
Example 1
A synthesis method of imidazo [4,5-b ] indole-2-thioketone derivative, which has the following reaction formula:
the synthesis method of the imidazo [4,5-b ] indole-2-thioketone derivative comprises the following steps: taking a 10mL test tube, adding 1-nitro-2- (phenylethynyl) benzene 2a (0.1 mmol), 1, 3-dimethyl thiourea 3a (0.3 mmol), triphenylphosphine (0.5 mmol), potassium carbonate (0.2 mmol) and acetonitrile (1 mL), stirring under the condition of nitrogen for reaction for 10 hours at 90 ℃, cooling to room temperature, and separating by silica gel column chromatography (eluent is ethyl acetate: petroleum ether volume ratio is 1:4), thereby obtaining a target product 1aa (27.5 mg, yellow solid, yield 90%).
The nuclear magnetic resonance hydrogen spectrum of the compound 1aa prepared in example 1 is shown in fig. 1; the nuclear magnetic resonance carbon spectrum of the compound 1aa prepared in example 1 is shown in fig. 2.
1 H NMR(400MHz,DMSO-d 6 ):δ7.53(s,1H),7.47–7.32(m,3H),7.30–7.22(m,3H),7.23–7.14(m,1H),6.76–6.66(m,2H),6.56(s,1H),3.08(s,3H),2.92(s,3H)； 13 C NMR(101MHz,DMSO):δ182.3,149.8,135.5,130.9,129.0,128.7,128.4,125.8,125.1,118.1,109.0,98.9,92.3,31.6,29.5.
Example 2
A synthesis method of imidazo [4,5-b ] indole-2-thioketone derivative, which has the following reaction formula:
the synthesis method of the imidazo [4,5-b ] indole-2-thioketone derivative comprises the following steps: 10mL test tubes were taken, 4-chloro-1-nitro-2- (phenylethynyl) benzene 2b (0.1 mmol), 1, 3-dimethylthiourea 3a (0.3 mmol), triphenylphosphine (0.5 mmol), potassium carbonate (0.2 mmol) and acetonitrile (1 mL) were added, the reaction was stirred under nitrogen for 10h at 90℃and cooled to room temperature after the reaction was completed, and the target product 1ba (36.6 mg, yellow solid, 96% yield) was obtained by silica gel column chromatography separation (eluent: ethyl acetate: petroleum ether: 1:4 by volume).
The nuclear magnetic resonance hydrogen spectrum of the compound 1ba prepared in example 2 is shown in fig. 3.
1 H NMR(400MHz,DMSO-d 6 ):δ7.73(s,1H),7.45–7.36(m,3H),7.26–7.20(m,4H),6.72(s,2H),3.07(s,3H),2.90(s,3H)； 13 C NMR(101MHz,DMSO):δ182.4,148.6,135.0,130.7,129.2,128.8,128.4,127.7,124.8,121.3,110.3,98.4,92.8,31.6,29.6.
Example 3
A synthesis method of imidazo [4,5-b ] indole-2-thioketone derivative, which has the following reaction formula:
a synthesis method of imidazo [4,5-b ] indole-2-thioketone derivative: 10mL test tubes are taken, 4-chloro-2-nitro-1 (phenylethynyl) benzene 2c (0.1 mmol), 1, 3-dimethylthiourea 3a (0.3 mmol), triphenylphosphine (0.5 mmol), potassium carbonate (0.2 mmol) and acetonitrile (1 mL) are added, the reaction is stirred for 10h at 90 ℃ under the condition of nitrogen, after the reaction is finished, the mixture is cooled to room temperature and separated by silica gel column chromatography (eluent is ethyl acetate with volume ratio of petroleum ether to be 1:4), and the target product 1ca (28.7 mg, yellow solid with the yield of 83%) is obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ7.85(s,1H),7.48–7.34(m,3H),7.29–7.21(m,3H),6.74–6.66(m,3H),3.06(s,3H),2.91(s,3H)； 13 C NMR(101MHz,DMSO):δ182.4,151.1,135.4,135.0,129.2,128.9,128.4,126.4,124.8,117.7,108.6,98.2,92.6,31.6,29.5.
Example 4
A synthesis method of imidazo [4,5-b ] indole-2-thioketone derivative, which has the following reaction formula:
the synthesis method of the imidazo [4,5-b ] indole-2-thioketone derivative comprises the following steps: 10mL test tubes were taken, 4-methoxy-1-nitro-2- (phenylethynyl) benzene 2d (0.1 mmol), 1, 3-dimethylthiourea 3a (0.3 mmol), triphenylphosphine (0.5 mmol), potassium carbonate (0.2 mmol) and acetonitrile (1 mL) were added, the reaction was stirred under nitrogen for 10h at 90℃and cooled to room temperature after the reaction was completed, and the product was isolated by silica gel column chromatography (eluent volume ratio ethyl acetate: petroleum ether: 1:4) to give the target product 1da (26.9 mg, yellow solid, yield 79%).
The nuclear magnetic resonance hydrogen spectrum of the compound 1da prepared in example 4 is shown in FIG. 4
1 H NMR(400MHz,DMSO-d 6 ):δ7.53(s,1H),7.43–7.42(m,3H),7.25(d,J＝7.6,Hz 2H),7.14(d,J＝9.0Hz,1H),6.43(s,1H),6.30-6.23(m,2H),3.73(s,3H),3.05(s,3H),2.90(s,3H)； 13 C NMR(101MHz,DMSO):δ182.1,162.2,151.3,135.6,128.9,128.7,128.4,125.7,118.4,103.8,98.5,94.8,92.6,55.6,31.6,29.5.
Example 5
A synthesis method of imidazo [4,5-b ] indole-2-thioketone derivative, which has the following reaction formula:
the synthesis method of the imidazo [4,5-b ] indole-2-thioketone derivative comprises the following steps: 10mL test tubes are taken, 4-methyl-2-nitro-1 (phenylethynyl) benzene 2e (0.1 mmol), 1, 3-dimethylthiourea 3a (0.3 mmol), triphenylphosphine (0.5 mmol), potassium carbonate (0.2 mmol) and acetonitrile (1 mL) are added, the reaction is stirred for 10h at 90 ℃ under the condition of nitrogen, after the reaction is finished, the mixture is cooled to room temperature and separated by silica gel column chromatography (eluent is ethyl acetate with volume ratio of petroleum ether to 1:4), and the target product 1ea (28 mg, yellow solid with 86 percent yield) is obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ7.46–7.31(m,4H),7.25(d,J＝7.8Hz,2H),7.11(d,J＝7.4Hz,1H),6.51(d,J＝8.7Hz,2H),6.46(s,1H),3.04(s,3H),2.89(s,3H),2.24(s,3H)； 13 C NMR(101MHz,DMSO):δ182.1,150.0,140.5,135.6,128.9,128.6,128.4,124.7,123.6,118.9,109.5,98.7,92.4,31.5,29.6,21.8.
Example 6
A synthesis method of imidazo [4,5-b ] indole-2-thioketone derivative, which has the following reaction formula:
the synthesis method of the imidazo [4,5-b ] indole-2-thioketone derivative comprises the following steps: 10mL test tubes are taken, 1- ((4-chlorophenyl) ethynyl) -2-nitrobenzene 2f (0.1 mmol), 1, 3-dimethyl thiourea 3a (0.3 mmol), triphenylphosphine (0.5 mmol), potassium carbonate (0.2 mmol) and acetonitrile (1 mL) are added, the reaction is stirred for 10h under the condition of nitrogen, after the reaction is finished, the mixture is cooled to room temperature and separated by silica gel column chromatography (the eluent is ethyl acetate: petroleum ether with the volume ratio of 1:4), and the target product 1fa (32 mg, yellow solid and the yield of 91%) is obtained.
The nuclear magnetic resonance hydrogen spectrum of the compound 1fa prepared in example 6 is shown in fig. 5.
1 H NMR(400MHz,DMSO-d 6 ):δ7.58(s,1H),7.50(d,J＝8.3Hz,2H),7.29–7.24(m,3H),7.23-7.14(m,1H),6.75–6.66(m,2H),6.63(s,1H),3.07(s,3H),2.90(s,3H)； 13 C NMR(101MHz,DMSO):δ182.3,149.5,134.6,133.8,131.0,130.4,128.7,125.6,125.0,118.3,109.1,98.9,91.8,31.5,29.5.
Example 7
A synthetic method of imidazo [4,5-b ] indole-2-thione, the reaction formula is:
the synthesis method of imidazo [4,5-b ] indole-2-thioketone comprises the following steps: 10mL test tubes were taken, 2g (0.1 mmol) of 1-nitro-2- (p-tolylethynyl) benzene, 3a (0.3 mmol) of 1, 3-dimethylthiourea, 0.5 mmol) of triphenylphosphine, 0.2mmol of potassium carbonate, acetonitrile (1 mL) were added, the mixture was stirred under nitrogen for 10h at 90℃until the reaction was completed, and the mixture was cooled to room temperature and separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether: volume ratio: 1:4) to obtain the objective product 1ga (35.6 mg, yellow solid, yield: 98%).
1 H NMR(400MHz,DMSO-d 6 ):δ7.47(s,1H),7.27–7.20(m,3H),7.20–7.11(m,3H),6.74–6.65(m,2H),6.49(s,1H),3.07(s,3H),2.90(s,3H),2.31(s,3H)； 13 C NMR(101MHz,DMSO):182.1,150.0,140.5,135.6,128.9,128.6,128.4,124.7,123.2,118.8,109.5,98.7,92.4,31.5,29.5,21.8.
Example 8
A synthesis method of imidazo [4,5-b ] indole-2-thioketone derivative, which has the following reaction formula:
the synthesis method of the imidazo [4,5-b ] indole-2-thioketone derivative comprises the following steps: 10mL test tubes were taken, 1- ((4-ethylphenyl) ethynyl) -2-nitrobenzene 2h (0.1 mmol), 1, 3-dimethylthiourea 3a (0.3 mmol), triphenylphosphine (0.5 mmol), potassium carbonate (0.2 mmol) and acetonitrile (1 mL) were added, the reaction was stirred under nitrogen for 10h at 90℃and cooled to room temperature after the reaction was completed, and the target product 1ha (34.1 mg, yellow solid, 98% yield) was obtained by silica gel column chromatography separation (eluent: ethyl acetate: petroleum ether: 1:4 by volume).
The nuclear magnetic resonance hydrogen spectrum of the compound 1ha prepared in example 8 is shown in fig. 6.
1 H NMR(400MHz,DMSO-d 6 ):δ7.47(s,1H),7.29–7.21(m,3H),7.17(d,J＝8.3Hz,3H),6.74–6.65(m,2H),6.51(s,1H),3.06(s,3H),2.90(s,3H),2.62(q,J＝7.7Hz,2H),1.19(t,J＝7.6,1.7Hz,3H)； 13 C NMR(101MHz,DMSO):δ182.2,149.8,144.5,132.7,130.8,128.4,128.1,125.8,125.0,118.0,109.0,98.7,92.3,31.6,29.5,28.3,15.9.
Example 9
A synthesis method of imidazo [4,5-b ] indole-2-thioketone derivative, which has the following reaction formula:
the synthesis method of the imidazo [4,5-b ] indole-2-thioketone derivative comprises the following steps: taking a 10mL test tube, adding 1- ((4-methoxyphenyl) ethynyl) -2-nitrobenzene 2i (0.1 mmol), 1, 3-dimethyl thiourea 3a (0.3 mmol), triphenylphosphine (0.5 mmol), potassium carbonate (0.2 mmol) and acetonitrile (1 mL), stirring under nitrogen for reaction for 10h at 90 ℃, cooling to room temperature after the reaction is finished, and separating by silica gel column chromatography (the eluent is ethyl acetate: petroleum ether with the volume ratio of 1:4) to obtain a target product 1ia (27.3 mg, yellow solid with the yield of 80%).
1 H NMR(400MHz,DMSO-d 6 ):δ7.46(s,1H),7.24(d,J＝7.4Hz,1H),7.16(d,J＝7.1Hz,3H),6.97(d,J＝8.6Hz,2H),6.73–6.64(m,2H),6.48(s,1H),3.76(s,3H),3.06(s,3H),2.89(s,3H)； 13 C NMR(101MHz,DMSO):δ182.1,159.9,149.7,130.8,129.7,127.1,125.9,125.0,118.0,114.1,109.0,98.5,92.2,55.7,31.50,29.5.
Example 10
A synthetic method of imidazo [4,5-b ] indole-2-thione, the reaction formula is:
the synthesis method of imidazo [4,5-b ] indole-2-thioketone comprises the following steps: 10mL test tubes are taken, 2- ((2-nitrophenyl) ethynyl) thiophene 2j (0.1 mmol), 1, 3-dimethyl thiourea 3a (0.3 mmol), triphenylphosphine (0.5 mmol), potassium carbonate (0.2 mmol) and acetonitrile (1 mL) are added, the reaction is stirred for 10h under the condition of nitrogen at 90 ℃, after the reaction is finished, the mixture is cooled to room temperature and separated by silica gel column chromatography (the eluent is ethyl acetate: petroleum ether with the volume ratio of 1:4), and the target product 1ja (34.4 mg, dark green solid with the yield of 97%) is obtained.
The nuclear magnetic resonance hydrogen spectrum of the compound 1ja prepared in example 10 is shown in fig. 7.
1 H NMR(400MHz,DMSO-d 6 ):δ7.67(s,1H),7.60(d,J＝3.9Hz,1H),7.28(d,J＝7.4Hz,1H),7.22–7.14(m,1H),7.11–7.04(m,1H),6.95(d,J＝3.6Hz,1H),6.81(s,1H),6.76–6.66(m,2H),3.08(s,3H),2.98(s,3H)； 13 C NMR(101MHz,DMSO):δ181.9,149.1,139.9,130.9,128.5,127.8,127.6,125.7,125.1,118.5,109.3,98.5,90.1,31.7,29.7.
Example 11
A synthesis method of imidazo [4,5-b ] indole-2-thioketone derivative, which has the following reaction formula:
the synthesis method of the imidazo [4,5-b ] indole-2-thioketone derivative comprises the following steps: taking a 10mL test tube, adding 1-nitro-2- (phenylethynyl) benzene 2a (0.1 mmol), 1, 3-diethyl thiourea 3b (0.3 mmol), triphenylphosphine (0.5 mmol), potassium carbonate (0.2 mmol) and acetonitrile (1 mL), stirring under nitrogen for reaction for 10h at 90 ℃, cooling to room temperature after the reaction is finished, and separating by silica gel column chromatography (the eluent is ethyl acetate: petroleum ether with the volume ratio of 1:4) to obtain a target product 1ab (30.8 mg, yellow solid with the yield of 87%).
The nuclear magnetic resonance hydrogen spectrum of the compound 1ab prepared in example 11 is shown in fig. 8.
1 H NMR(400MHz,DMSO-d 6 ):δ7.47(s,1H),7.45–7.34(m,3H),7.31(d,J＝7.7Hz,2H),7.26(d,J＝7.4Hz,1H),7.20–7.12(m,1H),6.75–6.63(m,2H),6.49(s,1H),3.76–3.55(m,3H),3.22–3.09(m,1H),1.11(t,J＝7.0Hz,3H),1.06(t,J＝6.9Hz,3H)； 13 C NMR(101MHz,DMSO):δ181.4,149.8,135.7,130.8,128.9,128.8,128.4,126.0,124.9,117.9,108.8,99.0,93.2,37.9,14.7,14.4.
Example 12
Under the conditions of example 1, the kinds of solvents and inorganic bases were adjusted, and the influence of different solvents and inorganic bases on the yield was examined, and the conditions and results are shown in Table 1.
TABLE 1
It can be seen that the solvent has the greatest effect on the reaction, and when the solvent is dimethyl sulfoxide or N, N-dimethylformamide, only trace amounts of products can be obtained; the inorganic base has poor effect compared with cesium carbonate, sodium hydroxide and potassium tert-butoxide, and the solvent and the inorganic base are preferred to realize the best yield.
Based on the importance of imidazo [4,5-b ] indole-2-thione in pharmaceutical chemistry research and a very limited and obviously limited synthesis method, the application develops a simple and efficient synthesis method of imidazo [4,5-b ] indole-2-thione, which has the advantages of easy preparation of raw materials, mild reaction conditions and no metal catalyst, and has very important research significance and application value.
The application provides a novel method for synthesizing imidazo [4,5-b ] indole-2-thioketone derivatives by using 2- (ethynyl) nitrobenzene in a metal-free catalytic system, which takes simple and easily obtained 2- (ethynyl) nitrobenzene and thiourea derivatives as raw materials, does not need a metal catalyst in the reaction, and has the advantages of simple operation, mild reaction condition, good functional group compatibility, high product yield, environmental protection and the like.
The imidazo [4,5-b ] indole-2-thioketone compound provided by the application has a complex structure, can provide convenience for further molecular structure transformation, and has important application value in the research direction of the medicinal chemical anti-hypoxia active compound.
It should be noted that the above embodiments are only for illustrating the technical solution of the present application and not for limiting the same, and although the present application 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 application may be modified or substituted without departing from the spirit and scope of the technical solution of the present application, which is intended to be covered in the scope of the claims of the present application.

Claims (10)

1. A method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system, which is characterized in that: comprising the steps of (a) a step of,
adding 2- (ethynyl) nitrobenzene compounds, thiourea compounds, triphenylphosphine and inorganic base into an organic solvent, heating and stirring, and performing rotary evaporation chromatography to separate and purify to obtain a target product imidazo [4,5-b ] indole-2-thione;
the inorganic base is any one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate and cesium carbonate;
the organic solvent is any one of acetonitrile, 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide;
the imidazo [4,5-b ] indole-2-thioketone compound of the target product is shown in a formula (I):
（Ⅰ）
the 2- (ethynyl) nitrobenzene compound is shown in a formula (II):
（Ⅱ）
the thiourea compound is shown in a formula (III):
（Ⅲ）
r in the formulae (I) - (III) 1 、R 2 、R 3 Are each independently a group, wherein R 1 Hydrogen, methoxy, alkyl, halogen; r is R 2 Methyl, ethyl, n-butyl, phenyl; r is R 3 Halogen substituted phenyl, alkyl substituted phenyl, thiophene, alkyl.
2. The method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to claim 1, characterized in that: the heating and stirring are carried out for 5-10 hours by heating to 400-500 rpm at 80-90 ℃.
3. A process for the synthesis of imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to claim 1 or 2, characterized in that: the rotary evaporation chromatography is used for separation and purification, wherein 100-200 mesh column chromatography silica gel is adopted for separation, and the developing agent is petroleum ether, ethyl acetate and ethyl acetate: the volume ratio of petroleum ether is 1: 40-1: 3.
4. a process for the synthesis of imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to claim 1 or 2, characterized in that: the volume mole ratio of the organic solvent to the 2- (ethynyl) nitrobenzene compound is as follows in mL: the mol ratio is 1:0.1.
5. The method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to claim 1, characterized in that: the molar ratio of the 2- (ethynyl) nitrobenzene compounds to the thiourea compounds is 1-3:3.
6. A process for the synthesis of imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to claim 1 or 5, characterized in that: the molar ratio of the 2- (ethynyl) nitrobenzene compounds to the thiourea compounds is 1:3.
7. The method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to claim 1, characterized in that: the molar ratio of the 2- (ethynyl) nitrobenzene compounds to the triphenylphosphine is 1-3:5.
8. A process for the synthesis of imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to claim 1 or 7, characterized in that: the molar ratio of the 2- (ethynyl) nitrobenzene compounds to the triphenylphosphine is 1:5.
9. The method for synthesizing imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to claim 1, characterized in that: the molar ratio of the 2- (ethynyl) nitrobenzene compound to the potassium carbonate is 1-3:2.
10. A process for the synthesis of imidazo [4,5-b ] indole-2-thione derivatives in a metal-free catalytic system according to claim 1 or 9, characterized in that: the molar ratio of the 2- (ethynyl) nitrobenzene compounds to the potassium carbonate is 1:2.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1041588A (en) * 1988-02-25 1990-04-25 拜尔公司 The imidazolone and the imidazolidinethione class that replace

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1041588A (en) * 1988-02-25 1990-04-25 拜尔公司 The imidazolone and the imidazolidinethione class that replace

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Title
Palladium-catalyzed one-pot cycloaddition reactions of thioureas with 3H-indol-3-ones generated in situ from 2-alkynyl arylazides: rapid and efficient access to imidazoloindolines;Li, Ping，等;Organic Chemistry Frontiers;第7卷(第21期);3480-3485 *

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