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CN118878457A - Preparation method of N-aryl-2-phenylseleno aromatic amine compound - Google Patents

Preparation method of N-aryl-2-phenylseleno aromatic amine compound Download PDF

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CN118878457A
CN118878457A CN202410675577.6A CN202410675577A CN118878457A CN 118878457 A CN118878457 A CN 118878457A CN 202410675577 A CN202410675577 A CN 202410675577A CN 118878457 A CN118878457 A CN 118878457A
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reaction
aryl
aromatic amine
cyclohexanone
phenylseleno
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韩思雨
王晶晶
吴戈
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Wenzhou Medical University
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Wenzhou Medical University
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Abstract

The invention relates to a preparation method of an N-aryl-2-phenylseleno aromatic amine compound, which comprises the steps of taking cyclohexanone, aromatic amine and diphenyl diseleno ether as reaction raw materials in an organic solvent under the condition of oxygen, and obtaining the N-aryl-2-phenylseleno aromatic amine compound through three-component serial reaction under the action of an oxidant and alkali. The method has simple reaction conditions, high yield and purity of the product, opens up a synthetic route and a method for preparing the N-aryl-2-phenylselenoamine compound, and has good application potential and research value.

Description

Preparation method of N-aryl-2-phenylseleno aromatic amine compound
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a preparation method of an N-aryl-2-phenylselenoaromatic amine compound.
Background
Ortho-substituted aryl selenides have potential not only as the basic backbone of numerous lead compounds, bioactive molecules and functional materials, but also as bioisosteres. Because of the presence of two different substituents at adjacent positions on the phenyl ring, conventional construction methods such as electrophilic substitution, coupling and C-H functionalization are quite challenging, require multiple reaction steps and face regioselectivity problems. In established methods, transition metal catalyzed C-H selenization is a relatively compact strategy. For example, transition metal catalyzed orthotopic C-H selenization of anilines has been reported to be achieved with the aid of directing groups. However, the need to install and remove directing groups reduces the efficiency of synthesis. In addition, the problems of expensive catalytic systems and metal residues in the drug inhibit post drug development. In this context, direct difunctional aromatic hydrocarbons become more attractive because it allows two different substituents to be introduced simultaneously in the ortho position of the benzene ring, enriching the diversity of molecular structures. The professor team reported a palladium catalyzed CATELLANI reaction of aryl iodides with selenate for the preparation of 2-arylseleno aromatic ketones. This method has high site selectivity, modularity and good air tolerance, but is limited to ortho-substituted aryl iodides. In addition, aryne is a reactive intermediate commonly used in the preparation of ortho-disubstituted aromatic hydrocarbons. Biju reports three-component demethylaminoselenization and oxyselenylation of aryne. These schemes are limited to specific substrates because nucleophilic addition to substituted arynes directly forms mixtures that are difficult to separate. Therefore, from the viewpoint of quickly constructing a diverse compound library in the current drug discovery, it would be of great value to develop an aromatic selenization bifunctional method that is widely applicable, readily available and site-selective.
In recent years, dehydroaromatization of cyclohexanone to build substituted aromatics has received widespread attention. In addition, cyclohexanone also acts as an effective arylating reagent, reducing reliance on unnatural aryl halides. Although many breakthrough results have been achieved, the dehydrofunctionalization of cyclohexanone has been focused mainly on the introduction of new functional groups at the carbonyl α -or ipso-position. However, the regioselective dehydrobifunctionalization of carbonyl α -and ipso-positions remains an unattainable goal. To our knowledge, the preparation of ortho-disubstituted aromatic hydrocarbons using a three-component deoxygenation difunctional reaction of cyclohexanone, nucleophile and electrophile has not been achieved. The continuing interest in selenium chemistry has prompted us to consider developing intermolecular selenization bifunctionalization of cyclohexanone. Therefore, the method is particularly important for preparing the N-aryl-2-phenylselenoaromatic amine compound by using raw materials which are simple and convenient to process and have low-cost and easily-obtained substrates, and particularly, the reaction for preparing the N-aryl-2-phenylselenoaromatic amine compound by using cyclohexanone which is low-cost and easily-obtained, stable and convenient to experimental operation as an arylating reagent is not reported until now, and the method still has the need of continuing research and exploration, which is the basis and the motive force for completing the invention.
Disclosure of Invention
The technical problem to be solved by the invention is the problem of a synthetic route of a preparation method of an N-aryl-2-phenylselenoaromatic amine compound.
In order to solve the technical problems, the invention provides the following technical scheme:
In an organic solvent, cyclohexanone, aromatic amine and diphenyl diselenide are used as reaction raw materials under the condition of oxygen, and the N-aryl-2-phenylseleno aromatic amine compound is obtained through three-component serial reaction under the action of an oxidant and alkali;
The above reaction process can be represented by the following reaction formula:
The molar ratio of the cyclohexanone to the aromatic amine to the diphenyl diselenide is 1:2:1.
(1) Oxidizing agent
The oxidant in the invention is hydrogen peroxide, N-fluoro-bis-benzene sulfonamide, 2, 3-dichloro-5, 6-dicyanobenzoquinone, N-iodo-succinimide or cupric chloride, preferably N-iodo-succinimide, and the dosage of the N-iodo-succinimide is 100% of the dosage of the cyclohexanone in terms of mole.
(2) Alkali
The alkali in the invention is sodium carbonate, potassium carbonate, cesium carbonate or silver carbonate, preferably potassium carbonate, and the dosage of the potassium carbonate and the dosage of the cyclohexanone are 20% based on the mol.
(3) Organic solvents
The reaction solvent in the invention is an organic solvent, and the organic solvent is at least one of dimethyl sulfoxide, N-dimethylformamide, 1, 2-dichloroethane, acetonitrile, toluene and tetrahydrofuran, preferably dimethyl sulfoxide.
(4) Reaction temperature
In the preparation method of the invention, the reaction temperature is 100 ℃.
(5) Reaction time
In the preparation method of the invention, the reaction time is 24 hours.
(6) Separation and purification
In a preferred embodiment, the post-treatment step after the end of the reaction may be the following method: 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 screwing off a solvent, separating a concentrate by column chromatography, taking a petroleum ether and ethyl acetate mixed solution as an eluent, collecting an eluent, and concentrating to obtain a target product.
The preparation method of the N-aryl-2-phenylseleno aromatic amine compound provided by the invention has the following beneficial effects:
a) The reaction is high in efficiency, high in yield and simple and convenient in post-treatment;
b) Using cheap and easily available cyclohexanone as an arylating reagent;
c) The cheap and easy N-iodosuccinimide is used as an oxidant;
The invention takes cyclohexanone, aromatic amine and diphenyl diselenide as reaction raw materials, and under the action of oxidant and alkali, the N-aryl-2-phenylseleno aromatic amine compound is obtained through three-component series reaction. The method has the advantages of cheap and easily obtained reaction raw materials, high yield and purity of the product, development of a synthetic route and a synthetic method for the preparation of the N-aryl-2-phenylselenoamine compound, and provision of a new idea for the molecular design and synthesis of the disubstituted maleimide derivative, and has important social significance and economic significance.
Detailed Description
The present invention will be described in detail by way of specific examples, but the purpose and purpose of these exemplary embodiments are merely to illustrate the present invention, and are not intended to limit the actual scope of the present invention in any way.
The data and purity of the novel compounds given in the examples below were identified by nuclear magnetic resonance.
Embodiment 1:
synthesis of N- (2- (phenylseleno) phenyl) pyridin-3-amine
Cyclohexanone (0.2 mmol,1.0 equiv), 3-aminopyridine (0.4 mmol,2.0 equiv), diphenyldiselenide (0.2 mmol,1.0 equiv), N-iodosuccinimide (0.2 mmol,1.0 equiv), potassium carbonate (0.04 mmol,0.2 equiv) and 2mL of dimethyl sulfoxide were added to the reaction tube at room temperature, followed by charging with oxygen and replacing three times, stirring at 100 ℃ for 24 hours. The reaction mixture was cooled, diluted with ethyl acetate, extracted with brine, the organic phase separated, dried over anhydrous sodium sulfate, filtered to a heart flask, and the solvent was then removed by spinning, and the product was isolated by column chromatography (eluent: petroleum ether: ethyl acetate 9:1) as a yellow liquid in 77% yield and 50.2mg by weight.
The data of nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3)：δ8.38(s,1H),8.25(s,1H),7.70(dd,J＝7.7,1.6Hz,1H),7.41(d,J＝8.2Hz,1H),7.36-7.20(m,8H),6.93(td,J＝7.4,1.5Hz,1H),6.54(s,1H).
the data for the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz,CDCl3)：δ144.09,143.22,141.97,138.94,138.18,130.90,130.58,130.38,129.57,126.97,125.98,123.78,121.79,118.39,115.65.
The high resolution mass spectrum data of the resulting product are as follows:
HRMS(ESI)：calcd for C17H15N2Se[M+H]+327.0395，found 327.0390.
Implementation 2:
Synthesis of N- (4-fluorophenyl) -2- (phenylseleno) aniline
Cyclohexanone (0.2 mmol,1.0 equiv), 4-fluoroaniline (0.4 mmol,2.0 equiv), diphenyldiselenide (0.2 mmol,1.0 equiv), N-iodosuccinimide (0.2 mmol,1.0 equiv), potassium carbonate (0.04 mmol,0.2 equiv) and 2mL of dimethyl sulfoxide were added to the reaction tube at room temperature, followed by charging with oxygen and replacing three times, and stirring at 100 ℃ for 24 hours. The reaction mixture was cooled, diluted with ethyl acetate, extracted with brine, the organic phase separated, dried over anhydrous sodium sulfate, filtered to a heart flask, and then the solvent was removed by spinning, and the product was isolated by column chromatography (eluent: petroleum ether: ethyl acetate 9:1) as a yellow liquid in 86% yield and 59mg by weight.
The data of nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3)：δ7.71(d,J＝7.6Hz,1H),7.36-7.32(m,2H),7.31-7.24(m,4H),7.15(d,J＝8.2Hz,1H),7.09-7.00(m,4H),6.85(t,J＝7.4Hz,1H),6.55(s,1H).
the data for the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz,CDCl3)：δ158.99(d,J＝242.0Hz),146.25,138.53,137.97,131.38,130.77,129.91,129.48,126.67,123.34(d,J＝8.0Hz),120.15,116.07(d,J＝22.6Hz),115.91,114.08.
The data for nuclear magnetic resonance fluorine spectrum of the resulting product are as follows:
19F NMR(375MHz,CDCl3)δ-119.83(1F)；
The high resolution mass spectrum data of the resulting product are as follows:
HRMS(ESI)：calcd for C18H15NFSe[M+H]+344.0348，found 344.0343.
Implementation 3:
synthesis of N- (4-chlorophenyl) -2- (phenylseleno) aniline
Cyclohexanone (0.2 mmol,1.0 equiv), 4-chloroaniline (0.4 mmol,2.0 equiv), diphenyldiselenide (0.2 mmol,1.0 equiv), N-iodosuccinimide (0.2 mmol,1.0 equiv), potassium carbonate (0.04 mmol,0.2 equiv) and 2mL of dimethyl sulfoxide were added to the reaction tube at room temperature, followed by charging with oxygen and replacing three times, stirring at 100 ℃ for 24 hours. The reaction mixture was cooled, diluted with ethyl acetate, extracted with brine, the organic phase separated, dried over anhydrous sodium sulfate, filtered to a heart flask, and then the solvent was removed by spinning, and the product was isolated by column chromatography (eluent: petroleum ether: ethyl acetate 9:1) as a yellow liquid in 88% yield and product weight of 63.2mg.
The data of nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3)：δ7.68(d,J＝7.6Hz,1H),7.35-7.23(m,9H),7.01(d,J＝8.6Hz,2H),6.89(t,J＝7.2Hz,1H),6.55(s,1H).
the data for the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz,CDCl3)：δ144.83,140.89,138.22,131.13,130.55,130.23,129.51,129.37,127.08,126.82,121.17,121.08,117.55,115.43.
The high resolution mass spectrum data of the resulting product are as follows:
HRMS(ESI)：calcd for C18H15NClSe[M+H]+360.0052，found 360.0044.
Implementation 4:
synthesis of N- (4-bromophenyl) -2- (phenylseleno) aniline
Cyclohexanone (0.2 mmol,1.0 equiv), 4-bromoaniline (0.4 mmol,2.0 equiv), diphenyldiselenide (0.2 mmol,1.0 equiv), N-iodosuccinimide (0.2 mmol,1.0 equiv), potassium carbonate (0.04 mmol,0.2 equiv) and 2mL of dimethyl sulfoxide were added to the reaction tube at room temperature, then oxygen was charged and replaced three times, and stirred at 100 ℃ for 24 hours. The reaction mixture was cooled, diluted with ethyl acetate, extracted with brine, the organic phase separated, dried over anhydrous sodium sulfate, filtered to a heart flask, and then the solvent was removed by spinning, and the product was isolated by column chromatography (eluent: petroleum ether: ethyl acetate 9:1) as a yellow liquid in 79% yield by weight of 63.6mg.
The data of nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3)：δ7.68(d,J＝7.9Hz,1H),7.38(d,J＝8.7Hz,2H),7.34-7.23(m,7H),6.95(d,J＝8.7Hz,2H),6.89(t,J＝6.3Hz,1H),6.53(s,1H).
the data for the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz,CDCl3)：δ144.58,141.45,138.15,132.28,131.07,130.51,130.28,129.51,126.85,121.29,121.24,117.83,115.65,114.31.
The high resolution mass spectrum data of the resulting product are as follows:
HRMS(ESI)：calcd for C18H15NBrSe[M+H]+403.9547，found 403.9538.
As can be seen from examples 1 to 4 above, when the method of the present invention is employed, an N-aryl-2-phenylselenoaromatic amine compound can be obtained in high yield and purity.
Examples 5 to8
Examples 5 to 8 were each carried out in the same manner as in example 1 except that the N-iodosuccinimide thereof was replaced with the following oxidizing agent, respectively, and the used oxidizing agent and the yields of the corresponding products were as shown in Table 1 below.
TABLE 1
Numbering device Oxidizing agent Reaction yield (%)
Example 5 Hydrogen peroxide Non-reaction
Example 6 N-fluoro bis-benzenesulfonamide Non-reaction
Example 7 2, 3-Dichloro-5, 6-dicyanobenzoquinone Non-reaction
Example 8 Copper chloride Non-reaction
As can be seen from table 1 above, when other oxidants were used, none of the target products were present, thus demonstrating that N-iodosuccinimide was the key factor in the success of the reaction and was most effective in the reaction system.
Examples 9 to 11
Examples 9 to 11 were each carried out in the same manner as in example 1 except that the potassium carbonate therein was replaced with the following base, respectively, and the yields of the base used and the corresponding products are shown in Table 2 below.
TABLE 2
Numbering device Alkali Reaction yield (%)
Example 9 Sodium carbonate 5
Example 10 Cesium carbonate 22
Example 11 Silver carbonate Non-reaction
As can be seen from Table 2 above, when sodium carbonate or cesium carbonate was used, the yield was reduced considerably, and when silver carbonate was used, it was not reacted at all, demonstrating that potassium carbonate was the key factor for the success of the reaction and was most effective for the reaction system.
Examples 12 to 16
Examples 12 to 16 were each carried out in the same manner as in example 1 except that the organic solvents dimethylsulfoxide therein were replaced with the following organic solvents, respectively, and the used organic solvents and the yields of the corresponding products were as shown in Table 3 below.
TABLE 3 Table 3
Numbering device Solvent(s) Reaction yield (%)
Example 12 N, N-dimethylformamide Non-reaction
Example 13 1, 2-Dichloroethane Non-reaction
Example 14 Acetonitrile Non-reaction
Example 15 Toluene (toluene) Non-reaction
Example 16 Tetrahydrofuran (THF) Non-reaction
From table 3 above, it can be seen that no product is present when other organic solvents are used, which proves that a suitable choice of organic solvent has a significant, or 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 to use a catalytic reaction system composed of an oxidizing agent (especially N-iodosuccinimide), a base (especially potassium carbonate) and a suitable organic solvent (especially dimethyl sulfoxide), cyclohexanone, aromatic amine and diphenyl diselenide are synthesized in high yield and high purity through three-component serial reaction under the oxygen condition, so that a novel synthetic route is provided for the efficient and rapid synthesis of the N-aryl-2-phenyldiselenide aromatic amine compound.
Finally, it should be noted that; the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme recorded in the previous embodiments is still modified in scientific research, or part or all of the technical features are replaced equivalently; such modifications and substitutions do not depart from the spirit of the invention.

Claims (6)

1. The preparation method of the N-aryl-2-phenylseleno aromatic amine compound is characterized in that cyclohexanone, aromatic amine and diphenyl diseleno ether are used as reaction raw materials in an organic solvent under the condition of oxygen, and the N-aryl-2-phenylseleno aromatic amine compound is obtained through three-component serial reaction under the action of an oxidant and alkali;
the cyclohexanone is:
The aromatic amine is as follows:
the diphenyl diselenide is as follows: phSeSePh A
The N-aryl-2-phenylselenoaromatic amine compound is as follows:
The organic solvent is dimethyl sulfoxide;
the oxidant is N-iodized succinimide;
The base is potassium carbonate.
2. The method of claim 1, wherein the molar ratio of cyclohexanone, aromatic amine and diphenyl diselenide is 1:2:1.
3. The process according to claim 1, wherein the amount of the oxidizing agent is 100% of the amount of cyclohexanone on a molar basis.
4. The process according to claim 1, wherein the base is used in an amount of 20% of the amount of cyclohexanone on a molar basis.
5. The process of claim 1, wherein the reaction temperature is 100 ℃.
6. The preparation method according to claim 1, wherein the reaction time is 24 hours.
CN202410675577.6A 2024-05-24 2024-05-24 Preparation method of N-aryl-2-phenylseleno aromatic amine compound Pending CN118878457A (en)

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