CN111978237A - Preparation method of 3-morpholinyl-4-arylseleno maleimide compound - Google Patents
Preparation method of 3-morpholinyl-4-arylseleno maleimide compound Download PDFInfo
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- CN111978237A CN111978237A CN202010816817.1A CN202010816817A CN111978237A CN 111978237 A CN111978237 A CN 111978237A CN 202010816817 A CN202010816817 A CN 202010816817A CN 111978237 A CN111978237 A CN 111978237A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/456—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
Abstract
The invention relates to a preparation method of 3-morpholinyl-4-arylseleno maleimide compound, which comprises the steps of taking arylboronic acid, selenium powder, morpholine and N-methylmaleimide as reaction raw materials in an organic solvent under the condition of oxygen, and carrying out series reaction on four components under the common synergistic catalysis action of a transition metal copper catalyst, a silver salt, a ligand and an alkali to obtain the 3-morpholinyl-4-arylseleno maleimide compound. The method has simple reaction conditions and high yield and purity of the product, develops a synthetic route and a method for preparing the 3-morpholinyl-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 preparation method of a 3-morpholinyl-4-arylseleno maleimide compound.
Background
3, 4-bifunctional maleimides are widely found in marine natural alkaloids and antitumor active molecules, candidate drug molecules and AIE fluorescent materials with important biological activities as core scaffolds, for example: g2 cell cycle checkpoint kinase Isogranula timeide, LPS-induced macrophage inhibitor Himanimide A, anti-breast cancer drug Camphoratamide B, specific Porcupine inhibitor, marine alkaloid aqabamycin G and liver x receptor agonist GSK 3987. In addition, maleimide can also be used for carrying out abundant and diverse functional group conversion to synthesize derivatives such as succinimide, tetrahydropyrrole, 2-pyrrolidone and the like. Therefore, the search for efficient construction of 3, 4-bifunctional maleimides from inexpensive and readily available raw materials has become one of the hot spots in current organic chemistry, pharmaceutical chemistry and material science research.
On the other hand, in consideration of the potential application value of the arylseleno ether compound in the research and development of drugs, the development of a method for introducing an arylseleno group into a maleimide molecular structure attracts the attention of synthetic chemists. The Baidiya topic group reports that transition metal ruthenium catalyzes the oxidative selenylation reaction of maleimide and diaryl diselenide, however, the pre-preparation of diaryl diselenide and the use of a noble metal ruthenium catalyst make the reaction not effectively applicable to the later modification of drug molecules, and reduce the discovery opportunities of innovative drug molecules. Therefore, a novel selenylation reagent is developed, and the direct catalysis of amine arylselenylation by maleimide is an effective strategy, and the efficient construction of carbon-nitrogen bonds and double carbon-selenium bonds and the introduction of medicine-containing molecules can be realized by one-step reaction. Recently, we have reported Copper-Catalyzed aminoselenylation of Maleimides (Oxidative amide polymerization of Maleimides via coater-Catalyzed Four-Component Cross-Coupling, Organic Letters 2019, 21, 3, 745-748). In consideration of the importance of the parent nucleus structures of the arylseleno and maleimide in the research and development of innovative drugs, the method is particularly important for preparing the 3-morpholinyl-4-arylseleno maleimide compound from raw materials which are simple and easy to process, cheap and easy to obtain substrates, and particularly for preparing the 3-morpholinyl-4-arylseleno maleimide compound by taking arylboronic acid which is cheap and easy to obtain, stable and convenient to operate in experiments as a phenylating reagent, so far, the method has not been reported, and the method still has the need of continuous research and exploration, which is the basis and the motive force 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-morpholinyl-4-arylseleno maleimide compound.
In order to solve the technical problems, the invention provides the following technical scheme:
a preparation method of 3-morpholinyl-4-arylseleno maleimide compound comprises the steps of taking arylboronic acid, selenium powder, morpholine and N-methylmaleimide as reaction raw materials in an organic solvent under the condition of oxygen, and obtaining the 3-morpholinyl-4-arylseleno maleimide compound through four-component series reaction under the common synergistic catalysis of a transition metal copper catalyst, a silver salt, a ligand and an alkali;
the above reaction process can be represented by the following reaction formula:
the mol ratio of the arylboronic acid to the selenium powder to the morpholine to the N-methylmaleimide is 3: 1.
(1) Transition metal copper catalyst
The transition metal copper catalyst in the invention is copper acetate, cuprous bromide, copper trifluoromethanesulfonate, cuprous chloride, cupric bromide or cuprous iodide, preferably cuprous iodide, and the dosage of the cuprous iodide is 20% of the dosage of the N-methylmaleimide in terms of molar amount.
(2) Silver salts
The silver salt in the invention is silver oxide, silver carbonate, silver acetate or silver nitrate, preferably silver carbonate, and the ratio of the usage amount of the silver salt to the usage amount of the N-methylmaleimide is 2: 1 by mol.
(3) Ligands
The ligand in the invention is triphenylphosphine, tricyclohexylphosphine, 1, 10-phenanthroline or 2, 2' -bipyridyl, and 1, 10-phenanthroline is preferred. The amount of the ligand is 20% of the amount of the N-methylmaleimide on a molar basis.
(4) Alkali
The alkali in the invention is at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate or sodium phosphate, preferably cesium carbonate, and the ratio of the dosage of the cesium carbonate to the dosage of the N-methylmaleimide is 3: 1 in terms of molar amount.
(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, 1, 4-dioxane, 1, 2-dichloroethane, acetonitrile, toluene and tetrahydrofuran, and preferably N, N-dimethylformamide.
(6) Reaction temperature
In the preparation method of the present invention, the reaction temperature is 120-140 ℃, and can be, for example, but not limited to, 120 ℃, 130 ℃ and 140 ℃, and the reaction temperature is preferably 140 ℃.
(7) 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 30 to 36 hours, such as 30 hours, 32 hours, 34 hours, or 36 hours, but is not limited thereto, and the reaction time is preferably 36 hours.
(8) Separating and purifying
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 water and ethyl acetate for extraction, drying an organic phase by using anhydrous sodium sulfate, filtering to a heart-shaped bottle, then spinning off the solvent, separating a concentrate by using column chromatography, taking a mixed solution of petroleum ether and ethyl acetate as an eluent, collecting the eluent, and concentrating to obtain a target product.
The preparation method of the 3-morpholinyl-4-arylseleno maleimide compound provided by the invention has the following beneficial effects:
a) the reaction has high efficiency, high yield and simple and convenient post-treatment;
b) selenium powder which is cheap and easy to obtain is used as a selenylation reagent;
c) cheap and easy copper is used as a catalyst;
according to the invention, arylboronic acid, selenium powder, morpholine and N-methyl maleimide are used as reaction raw materials, and under the co-concerted catalysis action of a transition metal copper catalyst, a silver salt, a ligand and an alkali, a four-component series reaction is carried out to obtain the 3-morpholinyl-4-arylseleno maleimide compound. The invention has cheap and easily obtained reaction raw materials and high yield and purity of the product, develops a synthetic route and a method for preparing the 3-morpholinyl-4-arylseleno maleimide compound, provides a new thought for molecular design and synthesis of the disubstituted maleimide derivative, 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.
Implementation 1:
synthesis of N-methyl-3-morpholinyl-4- (4-methylphenylseleno) maleimide compound
4-Methylphenylboronic acid (0.6mmol, 3.0equiv), selenium powder (0.6mmol, 3.0equiv), morpholine (0.6mmol, 3.0equiv), N-methylmaleimide (0.2mmol, 1.0equiv), cuprous iodide (0.04mmol, 0.2equiv), 1, 10-phenanthroline (0.04mmol, 0.2equiv), silver carbonate (0.4mmol, 2.0equiv), cesium carbonate (0.6mmol, 3.0equiv), and 2mL of N, N-dimethylformamide were added to a reaction tube at room temperature, then charged with oxygen and replaced three times, and stirred at 140 ℃ for 36 h. The reaction mixture was cooled, then diluted with ethyl acetate, extracted with brine, the organic phase separated, dried over anhydrous sodium sulfate, filtered to a heart-shaped flask, then the solvent was spun off and the product obtained was isolated by column chromatography (eluent: petroleum ether: ethyl acetate 9: 1) as a yellow liquid in 87% yield and 64mg of product weight.
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；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C16H18N2O3Se[M+H]+367.0562，found 367.0566.
implementation 2:
synthesis of N-methyl-3-morpholinyl-4- (4-methoxyphenylseleno) maleimide compound
4-methoxyphenylboronic acid (0.6mmol, 3.0equiv), selenium powder (0.6mmol, 3.0equiv), morpholine (0.6mmol, 3.0equiv), N-methylmaleimide (0.2mmol, 1.0equiv), cuprous iodide (0.04mmol, 0.2equiv), 1, 10-phenanthroline (0.04mmol, 0.2equiv), silver carbonate (0.4mmol, 2.0equiv), cesium carbonate (0.6mmol, 3.0equiv), and 2mL of N, N-dimethylformamide were added to a reaction tube at room temperature, then charged with oxygen and replaced three times, and stirred at 140 ℃ for 36 h. The reaction mixture was cooled, then diluted with ethyl acetate, extracted with brine, the organic phase separated, dried over anhydrous sodium sulfate, filtered to a flask of chicken heart, then the solvent was spun off and the product obtained was isolated by column chromatography (eluent: petroleum ether: ethyl acetate 9: 1) as a yellow liquid in 88% yield with 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)：7.33(d，J＝8.7Hz，2H)，6.82(d，J＝8.7Hz，2H)，4.18(t，J＝4.70Hz，4H)，3.79(s，3H)，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)：170.6，166.8，159.1，149.2，132.3，122.0，115.2，88.7，67.0，55.3，48.6，24.4；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C16H18N2O4Se[M+H]+383.0511，found 383.0517.
implementation 3:
synthesis of N-methyl-3-morpholinyl-4- (4-fluorobenzeneseleno) maleimide compound
4-Fluorophenylboronic acid (0.6mmol, 3.0equiv), selenium powder (0.6mmol, 3.0equiv), morpholine (0.6mmol, 3.0equiv), N-methylmaleimide (0.2mmol, 1.0equiv), cuprous iodide (0.04mmol, 0.2equiv), 1, 10-phenanthroline (0.04mmol, 0.2equiv), silver carbonate (0.4mmol, 2.0equiv), cesium carbonate (0.6mmol, 3.0equiv), and 2mL of N, N-dimethylformamide were added to a reaction tube at room temperature, then charged with oxygen and replaced three times, and stirred at 140 ℃ for 36 h. The reaction mixture was cooled, then diluted with ethyl acetate, extracted with brine, the organic phase separated, dried over anhydrous sodium sulfate, filtered to a heart-shaped flask, then the solvent was spun off and the product obtained was isolated by column chromatography (eluent: petroleum ether: ethyl acetate 9: 1) as a yellow liquid in 65% yield with a weight of 48mg product.
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)；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C15H15FN2O3Se[M+H]+371.0311，found 371.0301.
implementation 4:
synthesis of N-methyl-3-morpholinyl-4- (4-chlorophenylseleno) maleimide compound
4-Chlorobenzeneboronic acid (0.6mmol, 3.0equiv), selenium powder (0.6mmol, 3.0equiv), morpholine (0.6mmol, 3.0equiv), N-methylmaleimide (0.2mmol, 1.0equiv), cuprous iodide (0.04mmol, 0.2equiv), 1, 10-phenanthroline (0.04mmol, 0.2equiv), silver carbonate (0.4mmol, 2.0equiv), cesium carbonate (0.6mmol, 3.0equiv), and 2mL of N, N-dimethylformamide were added to a reaction tube at room temperature, then charged with oxygen and replaced three times, and stirred at 140 ℃ for 36 h. The reaction mixture was cooled, then diluted with ethyl acetate, extracted with brine, the organic phase separated, dried over anhydrous sodium sulfate, filtered to a flask of chicken heart, then the solvent was spun off and the product obtained was isolated by column chromatography (eluent: petroleum ether: ethyl acetate 9: 1) as a yellow liquid in 61% yield with a weight of 47mg product.
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；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C15H15ClN2O3Se[M+H]+387.0015，found 387.0008.
implementation 5:
synthesis of N-methyl-3-morpholinyl-4- (4-bromophenylseleno) maleimide compound
4-bromobenzeneboronic acid (0.6mmol, 3.0equiv), selenium powder (0.6mmol, 3.0equiv), morpholine (0.6mmol, 3.0equiv), N-methylmaleimide (0.2mmol, 1.0equiv), cuprous iodide (0.04mmol, 0.2equiv), 1, 10-phenanthroline (0.04mmol, 0.2equiv), silver carbonate (0.4mmol, 2.0equiv), cesium carbonate (0.6mmol, 3.0equiv), and 2mL of N, N-dimethylformamide were added to a reaction tube at room temperature, then charged with oxygen and displaced three times, stirred at 140 ℃ for 36 h. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, extracted with brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered to a heart-shaped flask, then the solvent was spun off, and the product was obtained by column chromatography (eluent: petroleum ether: ethyl acetate 9: 1) as a yellow solid with melting point of 111-.
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；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C15H15BrN2O3Se[M+H]+430.9510，found 30.9523.
implementation 6:
synthesis of N-methyl-3-morpholinyl-4- (4-trifluoromethylphenylseleno) maleimide compound
4-Trifluoromethylphenylboronic acid (0.6mmol, 3.0equiv), selenium powder (0.6mmol, 3.0equiv), morpholine (0.6mmol, 3.0equiv), N-methylmaleimide (0.2mmol, 1.0equiv), cuprous iodide (0.04mmol, 0.2equiv), 1, 10-phenanthroline (0.04mmol, 0.2equiv), silver carbonate (0.4mmol, 2.0equiv), cesium carbonate (0.6mmol, 3.0equiv), and 2mL of N, N-dimethylformamide were added to a reaction tube at room temperature, then charged with oxygen, and displaced three times, stirred at 140 ℃ for 36 h. The reaction mixture was cooled, then diluted with ethyl acetate, extracted with brine, the organic phase separated, dried over anhydrous sodium sulfate, filtered to a flask of chicken heart, then the solvent was spun off and the product obtained was isolated by column chromatography (eluent: petroleum ether: ethyl acetate 9: 1) as a yellow liquid in 19% yield with a weight of 16 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＝3.9Hz)，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)；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C16H15F3N2O3Se[M+H]+421.0279，found 421.0286.
from the above examples 1 to 6, it can be seen that 3-morpholino-4-arylseleno maleimide compounds can be obtained in high yield and high purity when the method of the present invention is employed.
Examples 7 to 11
Examples 7 to 11 were each carried out in the same manner as in example 1 except that cuprous iodide, which is a transition metal catalyst, was replaced with the following copper salt, respectively, and the yield of the copper salt compound used and the corresponding product were as shown in Table 1 below.
TABLE 1
| Numbering | Transition metal copper catalyst | Reaction yield (%) |
| Example 7 | Copper acetate | Is not reacted |
| Example 8 | Cuprous chloride | Is not reacted |
| Example 9 | Copper bromide | Is not reacted |
| Example 10 | Cuprous bromide | Is not reacted |
| Example 11 | Copper trifluoromethanesulfonate | Is not reacted |
As can be seen from table 1 above, when other copper salts were used, none of the target products were present, thus demonstrating that cuprous iodide is a key factor in the success of the reaction and is most effective for the reaction system.
Examples 12 to 14
Examples 12 to 14 were each carried out in the same manner as in example 1 except that the 1, 10-phenanthroline ligand was replaced with the following ligand, respectively, and the ligands used and the yields of the corresponding products were as shown in Table 2 below.
TABLE 2
| Numbering | Ligands | Reaction yield (%) |
| Example 12 | Triphenylphosphine | Is not reacted |
| Example 13 | Tricyclohexylphosphines | Is not reacted |
| Example 14 | 2, 2' -bipyridine | 10 |
As can be seen from Table 2 above, when triphenylphosphine or tricyclohexylphosphine is used, the reaction cannot take place, and when 2, 2' -bipyridine is used as a ligand, the yield is affected to some extent, thereby proving that 1, 10-phenanthroline is a key factor for the success of the reaction and is most effective for the reaction system.
Examples 15 to 17
Examples 15 to 17 were each carried out in the same manner as in example 1 except that silver carbonate therein was replaced with the following silver salt, respectively, and the yields of the silver salt used and the corresponding products were as shown in table 3 below.
TABLE 3
| Numbering | Silver salts | Reaction yield (%) |
| Example 15 | Silver oxide | Is not reacted |
| Example 16 | Silver acetate | Is not reacted |
| Example 17 | Silver nitrate | Is not reacted |
As can be seen from Table 3 above, none of the reactions occurred when other silver salts were used, thus demonstrating that the use of silver carbonate is a key factor in the success of the reaction and is most effective for the reaction system.
Examples 18 to 21
Examples 18-21 were each carried out in the same manner as in example 1 except that cesium carbonate therein was replaced with the following inorganic base, respectively, and the bases used and the yields of the corresponding products are shown in table 4 below.
TABLE 4
| Numbering | Alkali | Reaction yield (%) |
| Example 18 | Sodium carbonate | Is not reacted |
| Example 19 | Potassium carbonate | Is not reacted |
| Example 20 | Potassium phosphate | Is not reacted |
| Example 21 | Sodium phosphate | Is not reacted |
As can be seen from Table 4 above, when other inorganic bases were used, there was no product whatsoever, thus demonstrating that the use of cesium carbonate is a key factor in the success of the reaction and is most effective for the reaction system.
Examples 22 to 29
Examples 22 to 29 were each carried out in the same manner as in example 1 except that the organic solvents N, N-dimethylformamide therein were each replaced with the following organic solvents, and the organic solvents used and the yields of the corresponding products are shown in table 5 below.
TABLE 5
| Numbering | Solvent(s) | Reaction yield (%) |
| Example 22 | N, N-dimethyl acetamide | Is not reacted |
| Example 23 | N-methyl pyrrolidone | Is not reacted |
| Example 24 | Dimethyl sulfoxide | Is not reacted |
| Example 25 | 1, 4-dioxahexaalkane | Is not reacted |
| Example 26 | 1, 2-dichloroethane | Is not reacted |
| Example 27 | Acetonitrile | Is not reacted |
| Example 28 | Toluene | Is not reacted |
| Example 29 | Tetrahydrofuran (THF) | Is not reacted |
As can be seen from Table 5 above, the use of other strongly polar solvents such as dimethyl sulfoxide and N, N-dimethylacetamide, the non-polar solvent toluene, and the weakly coordinating solvents acetonitrile and tetrahydrofuran, without any product, demonstrates that the proper choice of organic solvent has a significant, even decisive influence on the reaction performance.
From the above, it is clear from all the above examples that when the method of the present invention is adopted with a catalytic reaction system consisting of a transition metal catalyst (especially cuprous iodide), a ligand (especially 1, 10-phenanthroline), a silver salt (especially silver carbonate), an inorganic base (especially cesium carbonate), and a suitable organic solvent (especially N, N-dimethylformamide), arylboronic acid, selenium powder, morpholine and N-methylmaleimide compounds are synthesized to obtain 3-morpholinyl-4-arylseleno maleimide compounds in high yield and high purity by four-component tandem reaction catalyzed by copper under oxygen conditions, and a completely new synthetic route is provided for efficient and rapid synthesis of the compounds.
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 (8)
1. A preparation method of 3-morpholinyl-4-arylseleno maleimide compound is characterized in that in an organic solvent, arylboronic acid, selenium powder, morpholine and N-methylmaleimide are used as reaction raw materials, and under the common synergistic catalysis action of a transition metal copper catalyst, a silver salt, a ligand and alkali, four components are subjected to a series reaction to obtain the 3-morpholinyl-4-arylseleno maleimide compound;
the arylboronic acid is:
the selenium powder is as follows: se
The morpholine is as follows:
the N-methylmaleimide is:
the 3-morpholinyl-4-arylseleno maleimide compound is as follows:
the copper catalyst is cuprous iodide;
the silver salt is silver carbonate;
the ligand is 1, 10-phenanthroline;
the base is cesium carbonate;
the organic solvent is N, N-dimethylformamide.
2. The method of claim 1, wherein the arylboronic acid, selenium powder, morpholine, and N-methylmaleimide are present in a molar ratio of 3: 1.
3. The production method according to claim 1, wherein the copper catalyst is used in an amount of 20% by mole based on the amount of the N-methylmaleimide.
4. The production method according to claim 1, wherein the ligand is used in an amount of 20% by mole based on the amount of the N-methylmaleimide.
5. The method according to claim 1, wherein the silver salt and the N-methylmaleimide are used in a molar ratio of 2: 1.
6. The process according to claim 1, wherein the base and N-methylmaleimide are used in a molar ratio of 3: 1.
7. The method as claimed in claim 1, wherein the reaction temperature is 120-140 ℃.
8. The process according to claim 1, wherein the reaction time is 30 to 36 hours.
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| CN114031537A (en) * | 2021-09-18 | 2022-02-11 | 温州医科大学 | Synthetic method of 3-deuterated methylthio-4-morpholinyl maleimide compound |
| CN114031538A (en) * | 2021-09-18 | 2022-02-11 | 温州医科大学 | Preparation method of 3-deuterated methylseleno-4-morpholinyl maleimide compound |
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| CN108863878A (en) * | 2018-02-19 | 2018-11-23 | 温州医科大学 | A kind of beta-hydroxy selenide compound and preparation method |
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| CN108863878A (en) * | 2018-02-19 | 2018-11-23 | 温州医科大学 | A kind of beta-hydroxy selenide compound and preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114031537A (en) * | 2021-09-18 | 2022-02-11 | 温州医科大学 | Synthetic method of 3-deuterated methylthio-4-morpholinyl maleimide compound |
| CN114031538A (en) * | 2021-09-18 | 2022-02-11 | 温州医科大学 | Preparation method of 3-deuterated methylseleno-4-morpholinyl maleimide compound |
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