CN111925310A - 3-amino-4-arylseleno maleimide compound and preparation method thereof - Google Patents
3-amino-4-arylseleno maleimide compound and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a 3-amido-4-arylseleno maleimide compound and a preparation method thereof, in an organic solvent and under the condition of oxygen, aromatic iodide, selenium powder, maleimide and secondary amine are taken as reaction raw materials, and the carbon-carbon double bond of the maleimide is simultaneously subjected to oxidative coupling reaction through relay reaction catalyzed by transition metal copper to obtain the 3-amido-4-arylseleno maleimide compound. The method has simple reaction conditions and high yield and purity of the product, develops a new synthetic route and method for preparing the 3-amido-4-arylseleno maleimide compound, and has good application potential and research value.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a 3-amido-4-arylseleno maleimide compound and a preparation method thereof.
Background
Maleimide as an important amide compound is widely present in natural products, bioactive molecules and clinical drug molecules, and the parent structure can also be used for preparing derivatives such as succinimide, pyrrolidine and lactam through various conversion reactions, so that how to efficiently and greenly synthesize the derivatives with maleimide skeletons is a target pursued by organic chemists based on the application of maleimide compounds in different fields. For example: the Pianxing professor of Zhongshan university utilizes an organic Base catalyst, takes 1, 4-dithio-2, 5-diol and maleimide as substrates, and prepares a chiral heterocyclic compound with a Tetrahydrothiophene skeleton structure (Diastereoscopic Synthesis of Biheterocyclic Tetrahydrothiophene derivative via Base-Catalyzed Cascade dye-Alder [3+2] cyclization reaction through Diastereoselective tandem Michael-Alder [3+2] cyclization reaction, wherein the compound has good biological and pharmaceutical activities through pharmacological activity research; in 2008, A.Yu.Simonov et al reported that (Synthesis of 4_ substistuted 3- [3- (bivalent amino methyl) indole-1-yl ] maleimides and study of the ability to inhibit the activity of the protein kinase C alpha, preservation of multiple drug resistance of tumor cells and cytoxicity, Russ.chem.Bull.2008, 57, 2011-2020), the use of 3-amino-4-arylmercaptomaleimide could inhibit protein kinase, prevent the development of tumor cell resistance and cytotoxicity.
Because of the importance of compounds containing maleimide structure, a great deal of research has been carried out on the synthesis of compounds, particularly 3-amino-4-arylmercaptomaleimide compounds, and a plurality of synthetic routes and methods have been explored:
in 2002, Dubinia, G.G. et al reported (Reactions of 3, 4-dichloromaleimides with N-and S-nucleophiles, Ukrains kii Khimichischii Zhurnal, 68, 47-51; 2002) that 3-amino-4-arylmercaptomaleimide compounds were obtained by refluxing 3, 4-dichloromaleimide, arylamine and thiophenol under triethylamine conditions, however, this reaction required expensive 3, 4-dichloromaleimide as a raw material and was liable to cause environmental pollution even with malodorous thiophenol, and the reaction formula was as follows:
2018, professor Zhaowei of the university of east Hua reports (Three-Component Coupling Reactions of Maleimides, Thiols, and Amines: One-Step Construction of 3, 4-heteotom-functionalized Maleimides by coater-Catalyzed C (sp2) -H Thioamidation, Advanced Synthesis & Catalysis, 2018, 360, 173;. 179) that the preparation of 3-amino-4-arylmercaptomaleimide target compounds is achieved by the Three-Component cascade reaction of transition metal Copper/oxygen Catalyzed maleimide, arylamine, and thiophenol, and that the use of malodorous thiophenol is likely to cause environmental pollution, as shown in the following reaction scheme:
in recent years, seleno-Maleimides have been reported, in 2017, Mahidudin Baidiya et al, university of Indian science, A Demonstrolation of Umpollung Strategy, org.Lett., 2017, 19, 1902-1905, reports that the expensive ruthenium is used to catalyze the synthesis of 3-arylseleno-maleimide with diaryldiselenide, as follows:
although the prior art can solve the arylselenylation reaction of maleimide, the further industrial application of the reaction and the pharmacological activity or biological activity research of molecular compounds are limited by using pre-prepared diaryl diselenide and expensive ruthenium catalyst in the reaction process, and the synthesis of a series of 3-amino-4-arylseleno maleimide compounds from carbon-carbon double bonds in a maleimide structure through a bifunctional reaction is not reported so far. Therefore, the method is particularly important for preparing the 3-amino-4-arylseleno maleimide compound from the raw materials which are simple and convenient, easy to process and cheap and easily available in substrate, and particularly, the method still has the need of continuous research and exploration by utilizing the four-component tandem reaction in which elemental selenium is used as a selenylation reagent to participate to synthesize the 3-amino-4-arylseleno maleimide compound, which is the basis and the power for completing the method.
Disclosure of Invention
The technical problem to be solved by the invention is the synthetic route problem of the preparation method of the 3-amido-4-arylseleno maleimide compound.
In order to solve the technical problems, the invention provides the following technical scheme:
a preparation method of 3-amido-4-arylseleno maleimide compound comprises the steps of taking aromatic iodide with a structure shown in a formula (I), selenium powder with a structure shown in a formula (II), maleimide compound with a structure shown in a formula (III) and secondary amine with a structure shown in a formula (IV) as reaction raw materials in an organic solvent under the condition of oxygen, and obtaining the 3-amido-4-arylseleno maleimide compound with a structure shown in a formula (V) through the oxidative coupling reaction of carbon-carbon double bonds in the maleimide structure under the catalysis of transition metal copper.
The above reaction process can be represented by the following reaction formula:
the molar ratio of the aromatic iodide with the structure shown in the formula (I), the selenium powder with the structure shown in the formula (II), the maleimide with the structure shown in the formula (III) and the secondary amine with the structure shown in the formula (IV) is 6: 2: 3.
(1) Aromatic iodides
The aromatic iodides in the invention comprise iodobenzene, 1-iodonaphthalene, 4-methyl iodobenzene, 4-fluoroiodobenzene, 4-chloroiodobenzene, 4-bromoiodobenzene, 4-nitroiodobenzene, 4-trifluoromethyl iodobenzene, 4-cyano iodobenzene and 3-iodothiophene.
(2) Maleimide compound
The maleimide compounds in the present invention include maleimide, N-phenylmaleimide, N-benzylmaleimide, N-cyclohexylmaleimide and N- (2-thienylmethyl) maleimide
(3) Secondary amines
The secondary amines in the present invention include morpholine, thiomorpholine, tetrahydropyrrole, cyclohexylimine, 4-piperidinemethanol and 4-piperidinecarboxylate.
(4) Transition metal catalyst copper
The transition metal catalyst copper in the invention is cupric acetate, cupric chloride, cupric bromide or cuprous iodide, preferably cupric acetate, and the dosage ratio of cupric acetate to the formula (II) is 0.1: 1-0.3: 1, preferably 0.1 in terms of molar weight.
(5) Organic solvent
The reaction solvent in the invention is an organic solvent, and the organic solvent is at least one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, ethyl acetate, pyridine, 1, 4-dioxane, 1, 2-dichloroethane, acetonitrile, toluene, tetrahydrofuran, ethanol, carbon tetrachloride, chloroform and N-butanol, preferably N-methylpyrrolidone.
(6) Alkali
The base in the present invention is an inorganic base, and the base is lithium carbonate, cesium carbonate, potassium carbonate, sodium acetate, lithium acetate, potassium phosphate, sodium tert-butoxide, lithium tert-butoxide or potassium tert-butoxide, and preferably sodium carbonate.
(7) Reaction temperature
In the preparation method of the present invention, the reaction temperature is 100 ℃ to 120 ℃, and can be, for example, but not limited to, 100 ℃, 110 ℃ and 120 ℃, and the reaction temperature is preferably 120 ℃.
(8) Reaction time
In the production method of the present invention, the reaction time is not particularly limited, and a suitable reaction time can be determined by, for example, detecting the residual percentage of the objective product or raw material by liquid chromatography, and is usually 14 to 18 hours, such as 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours, but is not limited thereto, and the reaction time is preferably 18 hours.
(9) Separating and purifying
The mixture obtained after the reaction can be further separated and purified to obtain a purer final product. The method for separation and purification is well known to those skilled in the art, and for example, extraction, column chromatography, distillation, filtration, centrifugation, washing, fractionation and adsorption, or a combination of at least two methods can be used for separation and purification, such as extraction and column chromatography.
Of course, if desired, the reaction mixture obtained can also be introduced directly into other processes for direct reaction to produce other products. Alternatively, the reaction mixture may be subjected to one or more of pretreatment, for example, concentration, extraction and distillation under reduced pressure, prior to introduction into other processes, to obtain a crude product or a pure product, which is then introduced into other processes.
In a preferred embodiment, the post-treatment step after the reaction is completed may be as follows: after the reaction is finished, cooling the reaction liquid, adding ethyl acetate for dilution, transferring the diluted solution into a separating funnel, extracting by saturated saline solution, separating out a water phase and an organic phase, extracting the water phase by ethyl acetate for 3 times, combining the organic phases, adding 5g of anhydrous sodium sulfate, standing for 30min, washing a filter cake by 5mL of ethyl acetate for 3 times each time, then spinning off the solvent, separating the concentrate by column chromatography (wherein the silica gel is 300-mesh 400-mesh silica gel), collecting eluent by taking the mixed liquid of petroleum ether and ethyl acetate as an eluent, and concentrating to obtain the target product.
The preparation method of the 3-amino-4-arylseleno maleimide provided by the invention has the following beneficial effects:
a) the reaction has high efficiency, high yield and simple and convenient post-treatment;
b) elemental selenium is used as a selenylation reagent to participate in the series reaction of the four components;
c) cheap and easy copper/oxygen is used as a catalytic system;
the 3-amido-4-arylseleno maleimide compound with the structure shown in the formula (V) is obtained by taking aromatic iodide with the structure shown in the formula (I), selenium powder with the structure shown in the formula (II), maleimide with the structure shown in the formula (III) and secondary amine with the structure shown in the formula (IV) as reaction raw materials and performing oxidative coupling reaction on carbon-carbon double bonds in the maleimide structure under the catalytic action of transition metal copper/oxygen. The synthesis method is an important development and supplement of the 3-amino-4-arylseleno maleimide synthesis method with simple operation and low cost, provides a new strategy for molecular design and synthesis of maleimide derivatives, and has important social and economic meanings.
Detailed Description
The present invention is described in detail below with reference to specific examples, but the use and purpose of these exemplary embodiments are merely to exemplify the present invention, and do not set forth any limitation on the actual scope of the present invention in any form, and the scope of the present invention is not limited thereto.
The data and purity of the novel compounds given in the following examples were determined by nuclear magnetic resonance.
Example 1
Synthesis of 1-methyl-3-morphinyl-4- (1-naphthylseleno) maleimide compound
1-iodonaphthalene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then oxygen was charged and replaced three times, stirred at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 88%, and a product weight of 70 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：8.10(d，J＝8.2Hz，1H)，7.82(d，J＝7.9Hz，1H)，7.70(d，J＝7.7Hz，1H)， 7.56-7.49(m，2H)，7.37-7.32(m，2H)，4.13(t，J＝4.70Hz，4H)，3.58(t，J＝4.70Hz，4H)，3.06(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.3，166.6，150.5，134.1，132.3，131.3，128.7，127.4，127.3，126.6，126.4， 126.1，125.5，85.8，67.0，48.5，24.5；
HRMS(ESI)：calcd for C19H18N2O3Se[M+H]+403.0562，found 403.0566。
example 2
Synthesis of 1-methyl-3-morphinyl-4- (4-methylphenylseleno) maleimide compound
4-methyliodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times with stirring at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was obtained by column chromatography (eluent: petroleum ether: ether ═ 8: 1) as a yellow liquid, with a yield of 95% and a product weight of 69 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.22(d，J＝8.0Hz，2H)，7.06(d，J＝8.0Hz，2H)，4.15(t，J＝4.70Hz，4H)，3.67 (t，J＝4.70Hz，4H)，3.03(s，3H)，2.29(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.5，166.8，149.6，136.7，135.9，130.3，130.2，129.9，128.5，87.8，66.9， 48.5，24.4，20.9；
HRMS(ESI)：calcd for C16H18N2O3Se[M+H]+367.0562，found 367.0568。
example 3
Synthesis of 1-methyl-3-morphinyl-4- (4-fluorophenylseleno) maleimide compound
4-Fluoroiodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then oxygen was charged and replaced three times, stirred at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 71%, and a product weight of 52 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.34-7.31(m，2H)，6.97(t，J＝8.7Hz，2H)，4.17(t，J＝4.70Hz，4H)，3.70(t， J＝4.70Hz，4H)，3.03(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.3，166.6，162.1(d，JF＝246.5Hz)，149.7，131.8(d，JF＝7.7Hz)，126.6(d， JF＝3.4Hz)，116.6(d，JF＝21.8Hz)，87.4，66.9，48.6，4.4；
the nmr spectra of the product obtained were as follows:
19F NMR(470MHz，CDCl3)：-115.1(s，1F)；
HRMS(ESI)：calcd for C15H15FN2O3Se[M+H]+371.0311，found 371.0317。
example 4
Synthesis of 1-methyl-3-morphinyl-4- (4-chlorophenylseleno) maleimide compound
4-Chlorodiobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times with stirring at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 74%, and a product weight of 57 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.23(dd，J＝16.5，8.7Hz，4H)，4.17(t，J＝4.70Hz，4H)，3.70(t，J＝4.70Hz， 4H)，3.04(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.2，166.5，150.0，132.8，130.7，130.6，129.6，86.4，66.9，48.6，24.5；
HRMS(ESI)：calcd for C15H15ClN2O3Se[M+H]+387.0015，found 387.0022。
example 5
Synthesis of 1-methyl-3-morphininyl-4- (4-bromophenylseleno) maleimide compound
4-bromoiodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times with stirring at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 55%, and a product weight of 47 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.36(d，J＝8.3Hz，2H)，7.18(d，J＝8.4Hz，2H)，4.17(t，J＝4.70Hz，4H)，3.70 (t，J＝4.70Hz，4H)，3.04(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.2，166.5，150.1，132.5，131.4，130.9，120.7，86.3，66.9，48.6，24.5；
HRMS(ESI)：calcd for C15H16BrN2O3Se[M+H]+430.9510，found 430.9509。
example 6
Synthesis of 1-methyl-3-morphinyl-4- (4-nitrophenylseleno) maleimide compound
4-Nitro iodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methyl maleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then oxygen was charged and replaced three times, stirred at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 47%, and a product weight of 37 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：8.09(d，J＝8.7Hz，2H)，7.40(d，J＝8.7Hz，2H)，4.19(t，J＝4.70Hz，4H)，3.73 (t，J＝4.70Hz，4H)，3.10(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：169.8，166.1，150.9，146.4，143.1，128.4，124.3，83.9，66.9，48.7，24.6；
HRMS(ESI)：calcd for C15H15N3O5Se[M+H]+398.0256，found 398.0259。
example 7
Synthesis of 1-methyl-3-morphinyl-4- (4-trifluoromethylphenylseleno) maleimide compound
4-Trifluoromethyiiodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv), and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen, and displaced three times, stirring at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was obtained by column chromatography (eluent: petroleum ether: ether ═ 8: 1) as a yellow liquid, with a yield of 38%, and a product weight of 32 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.48(d，J＝8.1Hz，2H)，7.38(d，J＝8.1Hz，2H)，4.18(t，J＝4.70Hz，4H)，3.71 (t，J＝4.70Hz，4H)，3.06(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.0，166.3，150.6，137.9，128.7(q，JF＝32.9Hz)，128.7，126.1(q，JF＝3.9 Hz)，124.0(q，JF＝270.4Hz)，85.0，66.9，48.6，24.5；
the nmr spectra of the product obtained were as follows:
19F NMR(470MHz，CDCl3)：-62.6(s，3F)；
HRMS(ESI)：calcd for C16H15F3N2O3Se[M+H]+421.0279，found 421.0280。
example 8
Synthesis of 1-methyl-3-morphinyl-4- (4-cyanophenylseleno) maleimide compound
4-Cyanoiodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then oxygen was charged and replaced three times, stirred at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 51%, and a product weight of 38 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.52(d，J＝8.3Hz，2H)，7.37(d，J＝8.3Hz，2H)，4.19(t，J＝4.70Hz，4H)，3.74(t，J＝4.70Hz，4H)，3.08(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：169.9，166.2，150.9，140.4，132.7，128.7，118.6，109.9，84.2，66.9，48.7，24.6；
HRMS(ESI)：calcd for C16H15N3O3Se[M+H]+378.0358，found 378.0360。
example 9
Synthesis of 1-methyl-3-morphinanyl-4- (3-thienyl) maleimide compound
3-iodothiophene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then oxygen was charged and replaced three times, stirred at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 82%, and a product weight of 59 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.32-7.31(m，1H)，7.21(d，J＝1.9Hz，1H)，7.05-7.04(m，1H)，4.19(t， J＝4.70Hz，4H)，3.72(t，J＝4.70Hz，4H)，3.03(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.4，166.7，149.1，130.2，126.7，124.8，124.5，88.1，66.9，48.6，24.4；
HRMS(ESI)：calcd for C13H14N2O3SSe[M+H]+358.9969，found 358.9970。
example 10
Synthesis of 3-morphinyl-4-phenylseleno maleimide compound
Iodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), maleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, stirred at 120 ℃ reaction temperature for 18 h. Cooling the reaction mixture, adding ethyl acetate for dilution, transferring the diluted solution into a separating funnel, extracting with saturated saline solution, separating out an aqueous phase and an organic phase, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, adding 5g of anhydrous sodium sulfate, standing for 30min, washing a filter cake with 5mL of ethyl acetate for 3 times each time, then spinning off the solvent, and performing column chromatography to obtain a product (eluent: petroleum ether: ether ═ 8: 1) which is a yellow solid and has a melting point: 190 ℃ and 191 ℃, the yield is 60 percent, and the weight of the product is 40 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，DMSO-D6)：10.9(s，1H)，7.32-7.27(m，4H)，7.21-7.18(m，1H)，4.03(t，J＝4.70Hz， 4H)，3.57(t，J＝4.70Hz，4H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，DMSO-D6)：170.4，167.5，150.7，132.7，129.4，128.2，126.0，85.5，66.1，48.0；
HRMS(ESI)：calcd for C14H14N2O3Se[M+H]+339.0249，found 339.0251。
example 11
Synthesis of 1-phenyl-3-morphinyl-4-phenylseleno maleimide compound
Iodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-phenylmaleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times with stirring at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 81%, and a product weight of 67 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.46-7.43(m，2H)，7.40-7.32(m，5H)，7.29-7.21(m，3H)，4.19(t，J＝4.70 Hz，4H)，3.69(t，J＝4.70Hz，4H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：169.1，165.5，149.2，131.9，131.8，129.9，129.5，128.9，127.7，126.9，126.3， 88.5，66.9，48.7；
HRMS(ESI)：calcd for C20H18N2O3Se[M+H]+415.0562，found 415.0567。
example 12
Synthesis of 1-benzyl-3-morphilinyl-4-phenylseleno maleimide compound
Iodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-benzylmaleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times with stirring at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 81%, and a product weight of 69 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.41-7.39(m，2H)，7.36-7.22(m，8H)，4.72(s，2H)，4.16(t，J＝4.70Hz，4H)， 3.66(t，J＝4.70Hz，4H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.0，166.3，149.7，136.5，132.3，129.5，129.4，128.6，128.6，127.7，126.7， 87.2，66.9，48.5，42.1；
HRMS(ESI)：calcd for C21H20N2O3Se[M+H]+429.0718，found 429.0719。
example 13
Synthesis of 1-cyclohexyl-3-morphinyl-4-phenylseleno maleimide compound
Iodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-cyclohexylmaleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times with stirring at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 83%, and a product weight of 70 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.30-7.28(m，2H)，7.26-7.23(m，2H)，7.19(t，J＝7.0Hz，1H)，4.11(t，J＝4.70 Hz，4H)，3.96(tt，J＝8.3，3.4Hz，1H)，3.66(t，J＝4.70Hz，4H)，2.10-2.03(m，2H)，1.82(d，J＝3.1Hz，2H)， 1.68-1.66(m，2H)，1.34-1.18(m，4H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.2，166.4，149.5，132.4，129.4，129.3，126.6，87.6，66.9，51.4，48.4，29.9， 26.0，25.2；
HRMS(ESI)：calcd for C20H24N2O3Se[M+H]+421.1031，found 421.1033。
example 14
Synthesis of 1- (2-thienylmethyl) -3-morphinyl-4-phenylseleno maleimide compound
Iodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N- (2-thienylmethyl) maleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times with stirring at 120 ℃ reaction temperature for 18 h. Cooling the reaction mixture, adding ethyl acetate for dilution, transferring the diluted solution into a separating funnel, extracting with saturated saline solution, separating out an aqueous phase and an organic phase, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, adding 5g of anhydrous sodium sulfate, standing for 30min, washing a filter cake with 5mL of ethyl acetate for 3 times each time, then spinning off the solvent, and performing column chromatography to obtain a product (eluent: petroleum ether: ether ═ 8: 1) which is a yellow solid and has a melting point: 58-59 deg.C, yield 82%, product weight 71 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.30-7.28(m，2H)，7.26-7.19(m，4H)，7.08(d，J＝3.0Hz，1H)，6.94-6.92(m， 1H)，4.87(s，2H)，4.13(t，J＝4.70Hz，4H)，3.63(t，J＝4.70Hz，4H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：169.5，165.9，149.6，138.3，132.2，129.5，129.4，127.6，126.8，126.7，125.7， 87.3，66.9，48.5，36.2；
HRMS(ESI)：calcd for C19H18N2O3SSe[M+H]+435.0282，found 435.0288。
example 15
Synthesis of 1-methyl-3-morphinyl-4-phenylseleno maleimide compound
Iodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times with stirring at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 85%, and a product weight of 60 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.31-7.30(m，2H)，7.26-7.23(m，2H)，7.20(t，J＝7.0Hz，1H)，4.16(t，J＝4.70 Hz，4H)，3.66(t，J＝4.70Hz，4H)，3.0(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.4，166.7，149.8，132.3，129.4，129.3，126.7，87.0，66.9，48.5，24.4
HRMS(ESI)：calcd for C15H16N2O3Se[M+H]+353.0405，found 353.0401。
example 16
Synthesis of 1-methyl-3-thiomorpholinyl-4-phenylseleno maleimide compound
Iodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), thiomorpholine (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, stirred at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was obtained by column chromatography (eluent: petroleum ether: ether ═ 8: 1) as a yellow liquid, yield 77%, product weight 56 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.31-7.30(m，2H)，7.26-7.23(m，2H)，7.21-7.18(m，1H)，4.35(t，J＝4.70Hz， 4H)，3.04(s，3H)，2.69(t，J＝4.70Hz，4H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.3，166.7，150.2，132.4，129.4，129.4，126.7，87.6，51.2，28.1，24.5；
HRMS(ESI)：calcd for C15H16N2O2SSe[M+H]+369.0177，found 369.0179。
example 17
Synthesis of 1-methyl-3-tetrahydropyrrole-4-phenylseleno maleimide compound
Iodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), tetrahydropyrrole (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, stirred at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 74%, and a product weight of 50 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.31(d，J＝7.4Hz，2H)，7.22(t，J＝7.3Hz，2H)，7.15(t，J＝7.2Hz，1H)，4.03 (t，J＝6.8Hz，4H)，3.06(s，3H)，1.90(t，J＝6.8Hz，4H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：171.4，166.2，149.9，135.0，129.2，128.8，126.1，82.2，51.4，25.1，24.3；
HRMS(ESI)：calcd for C15H16N2O2Se[M+H]+337.0456，found 337.0458。
example 18
Synthesis of 1-methyl-3-cycloheptylamine-4-phenylseleno maleimide compound
Iodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), cycloheximide (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, stirred at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 80%, and a product weight of 58 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.30(d，J＝7.7Hz，2H)，7.21(t，J＝7.3Hz，2H)，7.15(t，J＝7.2Hz，1H)，4.07 (t，J＝6.1Hz，4H)，3.04(s，3H)，1.80-1.79(m，4H)，1.57-1.56(m，4H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.9，166.2，150.5，134.2，129.2，128.8，126.1，82.7，52.9，28.4，26.3，24.4；
HRMS(ESI)：calcd for C17H20N2O2Se[M+H]+365.0769，found 365.0770。
example 19
Synthesis of 1-methyl-3- (4-piperidinemethanol) -4-phenylselenylmaleimide compound
Iodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), 4-piperidinemethanol (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, stirred at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 58% and a product weight of 44 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.32-7.30(m，2H)，7.24-7.21(m，2H)，7.18-7.16(m，1H)，5.18(d，J＝13.3Hz， 2H)，3.46(d，J＝5.9Hz，2H)，3.04(s，3H)，1.82-1.79(m，3H)，1.64(s，2H)，1.29-1.23(m，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.7，166.8，150.9，133.0，129.3，129.2，126.4，85.5，67.1，48.7，38.1，29.3， 24.4；
HRMS(ESI)：calcd for C17H20N2O3Se[M+H]+381.0718，found 381.0721。
example 20
Synthesis of 1-methyl-3- (4-piperidinecarboxylate) -4-phenylselenemaleimide compound
Iodobenzene (0.6mmol, 3equiv), selenium powder (0.6mmol, 3equiv), N-methylmaleimide (0.2mmol, 1equiv), methyl 4-piperidinecarboxylate (0.3mmol, 1.5equiv), copper acetate (0.02mmol, 0.1equiv), sodium carbonate (0.8mmol, 4equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, stirred at 120 ℃ reaction temperature for 18 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 79%, and a product weight of 64 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.32-7.30(m，2H)，7.24-7.22(m，2H)，7.19-7.17(m，1H)，4.87(dt，J＝13.6， 3.6Hz，2H)，3.68(s，3H)，3.37-3.32(m，2H)，3.04(s，3H)，2.62-2.56(m，1H)，1.97-1.94(m，2H)，1，80-1.73(m， 2H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：174.2，170.6，166.7，150.6，132.7，129.3，129.3，126.5，86.4，51.9，47.9，40.2， 28.5，24.4；
HRMS(ESI)：calcd for C18H20N2O4Se[M+H]+409.0667，found 409.0668。
as can be seen from the above examples 1 to 20, when the method of the present invention is employed, 3-amino-4-arylseleno maleimide compounds can be obtained in high yield and high purity.
Examples 21 to 23
Examples 21 to 23 were each carried out in the same manner as in example 1 except that the transition metal catalyst copper acetate was replaced with the following copper salt, respectively, and the copper salt compounds used and the yields of the corresponding products were as shown in Table 1 below.
TABLE 1
As can be seen from Table 1 above, when other copper salts were used, cuprous iodide was able to react smoothly but the yield of the product decreased significantly, while cupric chloride and cupric bromide were not able to catalyze the reaction thereby demonstrating that cupric acetate is a key factor in the success of the reaction and is most effective for the reaction system.
Examples 24 to 37
Examples 24 to 37 were carried out in the same manner as in example 1 except that the organic solvent N-methylpyrrolidone was replaced with the following organic solvents, respectively, and the organic solvents used and the yields of the corresponding products were as shown in Table 2 below.
TABLE 2
| Numbering | Solvent(s) | Reaction yield (%) |
| Example 24 | Dimethyl sulfoxide | 24 |
| Example 25 | N, N-dimethyl acetamide | 19 |
| Example 26 | Methylene dichloride | Is not reacted |
| Example 27 | Ethyl acetate | Is not reacted |
| Example 28 | Pyridine compound | Is not reacted |
| Example 29 | 1, 4-dioxahexaalkane | Is not reacted |
| Example 30 | 1, 2-dichloroethane | Is not reacted |
| Example 31 | Acetonitrile | Is not reacted |
| Example 32 | Toluene | Is not reacted |
| Example 33 | Tetrahydrofuran (THF) | Is not reacted |
| Example 34 | Ethanol | Is not reacted |
| Example 35 | Carbon tetrachloride | Is not reacted |
| Example 36 | Chloroform | Is not reacted |
| Example 37 | N-butanol | Is not reacted |
As can be seen from Table 2 above, when other organic solvents were used, the reaction was allowed to occur except in the strongly polar solvent, dimethyl sulfoxide and N, N-dimethylacetamide, but the yield was still reduced; without any product under non-polar or even weakly coordinating solvent conditions. This demonstrates that the proper choice of organic solvent has a significant, even decisive influence on whether the reaction can proceed.
Examples 38 to 39
Examples 38 to 39 were each carried out in the same manner as in example 1 except that the alkali sodium carbonate therein was replaced with the following inorganic base, respectively, and the yields of the alkali compound and the corresponding product used were as shown in the following table 3, respectively, demonstrating that sodium carbonate is a key factor in the success of the reaction.
TABLE 3
| Numbering | Alkali | Reaction yield (%) |
| Example 38 | Cesium carbonate | Is not reacted |
| Example 39 | Lithium carbonate | Is not reacted |
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments are modified or some or all of the technical features are equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (7)
1. A preparation method of a 3-amido-4-arylseleno maleimide compound is characterized in that in an organic solvent and under the condition of oxygen, an aromatic iodide with a structure shown in a formula (I), selenium powder with a structure shown in a formula (II), maleimide with a structure shown in a formula (III) and secondary amine with a structure shown in a formula (IV) are used as reaction raw materials, and under the catalysis of transition metal copper, the 3-amido-4-arylseleno maleimide compound with the structure shown in a formula (V) is obtained through the oxidative coupling reaction of carbon-carbon double bonds in the maleimide structure.
The aromatic iodide is iodobenzene, 1-iodonaphthalene, 4-methyl iodobenzene, 4-fluoroiodobenzene, 4-chloroiodobenzene, 4-bromoiodobenzene, 4-nitroiodobenzene, 4-trifluoromethyl iodobenzene, 4-cyano iodobenzene and 3-iodothiophene;
the maleimide is maleimide, N-phenylmaleimide, N-benzylmaleimide, N-cyclohexylmaleimide and N- (2-thienylmethyl) maleimide;
the secondary amine is morpholine, thiomorpholine, tetrahydropyrrole, cyclohexylimine, 4-piperidine methanol and 4-piperidine methyl formate;
the copper catalyst is copper acetate;
the alkali is sodium carbonate;
the organic solvent is N-methyl pyrrolidone.
2. The process according to claim 1, wherein the copper catalyst is used in an amount of 1 to 15% by mole based on the amount of the compound of formula (III).
3. The method according to claim 1, wherein the amount of the base is 400% of the amount of the compound of formula (III).
4. The method of claim 1, wherein: the molar ratio of the aromatic iodide with the structure shown in the formula (I), the selenol with the structure shown in the formula (II), the maleimide with the structure shown in the formula (III) and the secondary amine with the structure shown in the formula (IV) is 6: 2: 3.
5. The method as claimed in claim 1, wherein the range of temperature is 100-120 ℃.
6. The method according to claim 1, wherein the reaction time is 14 to 18 hours.
7. The method of claim 1, wherein: after the reaction is finished, cooling the reaction liquid, adding an extracting agent for extraction, separating out a water phase and an organic phase, taking the organic phase containing the extracting agent and a target product, drying the organic phase by using anhydrous sodium sulfate, concentrating under reduced pressure, separating the concentrate by using column chromatography, wherein the silica gel is 300-mesh 400-mesh silica gel, collecting eluent by using mixed liquid of petroleum ether and ether with the volume ratio of 95: 5 as eluent, and carrying out rotary evaporation on the solvent to obtain the 3-amido-4-arylseleno maleimide compound shown as the formula (V).
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| CN115353477A (en) * | 2022-01-19 | 2022-11-18 | 温州医科大学 | Preparation method of bis-seleno-maleimide compound |
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