阅读说明：本技术 2,3-二氢-1,2-二氮环丁烯氮氧化物及其制备方法 (2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride and preparation method thereof ) 是由 王振华 袁伟成 沈力文 赵建强 游勇 于 2021-09-18 设计创作，主要内容包括：本发明公开了一类2,3-二氢-1,2-二氮环丁烯氮氧化物及其制备方法,属于有机合成领域,所述制备方法为向α-卤代苯乙酮肟、氨基甲酸酯及碱的混合物中加入有机溶剂,反应在一定温度下搅拌2-24小时,反应完成后,分离纯化即得；本发明通过分步的[3+1]环加成反应,实现了2,3-二氢-1,2-二氮环丁烯氮氧化物的合成,该类化合物作为为典型的1,3-偶极子可用于1,3-偶极环加成反应构建其他一系列杂环化合物；本发明的制备方法具有反应条件温和、转化效率高、操作简便及底物适应范围广等优点。(The invention discloses a 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride and a preparation method thereof, belonging to the field of organic synthesis α Adding an organic solvent into a mixture of halogenated acetophenone oxime, carbamate and alkali, reacting for 2-24 hours at a certain temperature, and separating and purifying after the reaction is finished; the invention passes through stepwise [3+1]]The cycloaddition reaction realizes the synthesis of 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride, and the compound can be used as a typical 1, 3-dipole for constructing other series of heterocyclic compounds by the 1, 3-dipolar cycloaddition reaction; the preparation method has the advantages of mild reaction conditions, high conversion efficiency, simple and convenient operation, wide substrate application range and the like.)

A2, 3-dihydro-1, 2-diazocyclobutene nitroxide characterized by the structure shown in the following structural formula:

in the above structural formula, R¹The group is selected from one of aryl, heteroaryl and condensed aryl; r²The group is selected from aralkyl, straight-chain alkyl, branched-chain alkyl or cycloalkyl as a protecting group.

2. The 2, 3-dihydro-1, 2-diazocyclobutene nitroxide of claim 1, wherein: the R is¹The group is selected from one of phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-methylphenyl, m-chlorophenyl, m-bromophenyl, m-cyanophenyl, m-methylphenyl, m-methoxyphenyl, 2, 5-dimethylphenyl, 3, 4-dichlorophenyl, 2-naphthyl, 2-benzofuran and 2-benzothiophene; the R is²One selected from benzyl, propyl, isopropyl, butyl, isobutyl, hexyl, allyl, cyclopentyl, 2-chloroethyl and 2,2, 2-trichloroethyl.

3. The method for preparing 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride according to claim 1 or 2, characterized in that, alpha-halogenated acetophenone oxime, carbamate and alkali are respectively weighed and mixed, an organic solvent is added under stirring, the reaction is continuously stirred until the reaction is completed, and then separation and purification are carried out to obtain the compound;

the alpha-halogenated acetophenone oxime has the following structure:

wherein R is¹The group is selected from aryl, heteroaryl and condensed aryl; the R group is selected from various types of leaving groups;

the carbamate has the following structure:

wherein R is²The radicals are selected from aralkyl, linear alkyl, branched alkyl, cycloalkyl.

4. A method of preparation according to claim 3, wherein the leaving group is selected from chlorine, bromine.

5. The method according to claim 3, wherein the organic solvent is selected from one or more of dichloromethane, chloroform, 1, 2-dichloroethane, methyl tert-butyl ether, toluene, methanol, and acetonitrile, preferably 1, 2-dichloroethane.

6. The method according to claim 3, wherein the base is used in an amount of 1.1 to 5.0 equivalents, preferably 4.0 equivalents.

7. The method according to claim 3, wherein the molar ratio of the α -haloacetophenone oxime to the carbamate is 1:1 to 4:1, preferably 2: 1.

8. The method according to claim 3, wherein the concentration of the carbamate is 0.05 to 0.4mol/L, preferably 0.10 mol/L.

9. The method according to claim 3, wherein the reaction temperature is 0 to 70 ℃, preferably 50 ℃.

10. The method according to claim 3, wherein the reaction time is 2 to 48 hours, preferably 4 hours.

Technical Field

The invention relates to the field of organic synthesis, in particular to a 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride and a preparation method thereof.

Background

The nitrogen-containing quaternary heterocyclic compound is widely existed in clinical medicines and bioactive compounds, for example, the beta-lactam antibiotics including cephalosporins, penicillins and other medicines contain a beta-lactam core skeleton structure, and in addition, the quaternary nitrogen-containing heterocyclic compound can also be used as a ligand for metal-catalyzed chemical transformation or as a key intermediate for synthesis of other nitrogen-containing heterocyclic compounds. Based on this, the college construction of quaternary nitrogen-containing heterocycles has attracted increasing attention from chemical workers.

As a special class of nitrogen-containing heterocycles with high ring tension, the 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride quaternary ring contains two nitrogen atoms, and the synthesis of the compounds still faces huge challenges at present. The traditional method for synthesizing 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride has only one example at present, and the method mainly utilizes the ring expansion reaction of aziridine, but the synthesis method has low yield and poor substrate adaptability.

So far, no further reports exist on a universal and efficient method for synthesizing 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride, and based on the method, the development of an efficient synthesis method for constructing the quaternary nitrogen heterocyclic skeleton is very necessary.

Disclosure of Invention

The invention aims to provide 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride, which is a typical 1, 3-dipole and can be used for 1, 3-dipolar cycloaddition reaction to construct other series of heterocyclic compounds.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows: 2, 3-dihydro-1, 2-diazocyclobutene nitroxide having the structure shown by the following structural formula:

in the above structural formula, R¹The group is selected from one of aryl, heteroaryl and condensed aryl; r²The group is selected from aralkyl, straight-chain alkyl, branched-chain alkyl or cycloalkyl as a protecting group.

As a preferred technical scheme: the R is¹The group is selected from one of phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-methylphenyl, m-chlorophenyl, m-bromophenyl, m-cyanophenyl, m-methylphenyl, m-methoxyphenyl, 2, 5-dimethylphenyl, 3, 4-dichlorophenyl, 2-naphthyl, 2-benzofuran and 2-benzothiophene; the R is²One selected from benzyl, propyl, isopropyl, butyl, isobutyl, hexyl, allyl, cyclopentyl, 2-chloroethyl and 2,2, 2-trichloroethyl.

The invention provides a brand-new 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride, which is a typical 1, 3-dipole and can be used for 1, 3-dipole cycloaddition reaction to construct other series of heterocyclic compounds.

The second purpose of the invention is to provide the preparation method of the 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride, so as to solve the problems of low synthesis efficiency, poor substrate adaptation and the like of the traditional method for synthesizing the compounds;

the preparation method of the invention can be used for simply and conveniently synthesizing the 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride. Lays a certain foundation for exploring the application of the compound in the field of constructing other nitrogen-containing heterocycles.

The technical scheme is that quantitative alpha-halogenated acetophenone oxime, carbamate and alkali are sequentially weighed, then an organic solvent is added into a mixture of the alpha-halogenated acetophenone oxime, the carbamate and the alkali, the mixture is stirred for 2 to 48 hours at a certain temperature for reaction, and after the reaction is finished, separation and purification are carried out to obtain the alpha-halogenated acetophenone oxime

The reaction formula is as follows:

the alpha-halogenated acetophenone oxime has the following structure:

wherein R is¹The radicals are selected from aryl radicals,Heteroaryl, fused aryl; the R group is selected from various leaving groups, mainly comprising chlorine, bromine and the like.

The carbamate has the following structure:

wherein R is²The radicals are selected from aralkyl, linear alkyl, branched alkyl, cycloalkyl.

The invention realizes the preparation of the 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride through the stepwise [3+1] cycloaddition reaction.

As a preferred technical scheme: the organic solvent is selected from one or more of dichloromethane, chloroform, 1, 2-dichloroethane, methyl tert-butyl ether, toluene, methanol and acetonitrile, and preferably 1, 2-dichloroethane. Because the reaction yield is highest in this solvent.

As a preferred technical scheme: the amount of the alkali used is 1.1 to 5.0 equivalents at the minimum, and 4.0 equivalents is preferred. Experiments prove that the consumption of alkali is obviously reduced, and the yield is reduced; the yield of the reaction is not further improved by increasing the amount of base.

As a preferred technical scheme: the molar ratio of the alpha-halogenated acetophenone oxime to the carbamate is 1: 1-4: 1, preferably 2: 1. Experiments prove that: at a molar ratio of 2:1, the reaction gives better results, i.e. the highest yields and the savings in raw materials. The reaction molar ratio is reduced, and the reaction yield is reduced; the reaction yield is not improved by increasing the reaction molar ratio, but excessive alpha-halogenated acetophenone oxime is wasted.

As a preferred technical scheme: the concentration of the carbamate is 0.05-0.4 mol/L, and preferably 0.10 mol/L. At this concentration, the reaction is carried out in higher yield while ensuring a precursor with less solvent.

As a preferred technical scheme: the reaction temperature is 0 to 70 ℃ and more preferably 50 ℃. On the premise of ensuring better reaction yield, the reaction energy consumption is lower.

As a preferred technical scheme: the reaction time is 2 to 48 hours, preferably 4 hours.

The invention has the advantages that: the synthesis of 2, 3-dihydro-1, 2-dinitrogen cyclobutene oxynitride is realized through stepwise [3+1] cycloaddition reaction promoted by alkali, and the compound can be used for 1, 3-dipolar cycloaddition reaction to construct other series of heterocyclic compounds as a typical 1, 3-dipole; the method has the advantages of mild reaction conditions, high conversion efficiency, simple and convenient operation, wide substrate application range and the like.

Drawings

FIG. 1 is a hydrogen spectrum of the compound obtained in example 1;

FIG. 2 is a carbon spectrum of the compound obtained in example 1;

FIG. 3 is a hydrogen spectrum of the compound obtained in example 5;

FIG. 4 is a carbon spectrum of the compound obtained in example 5

FIG. 5 is a hydrogen spectrum of the compound obtained in example 6;

FIG. 6 is a carbon spectrum of the compound obtained in example 6.

Detailed Description

The invention will be further explained with reference to the drawings.

Example 1: preparation of the Compound of the formula

The preparation method comprises the following steps: in a reaction tube, benzyl carbamate (0.1mmol reactant concentration of 0.1mol/L) was dissolved in dichloromethane (1.0mL), and then a reaction mixture of α -bromoacetophenone oxime (0.12mmol) and 1, 8-diazabicycloundec-7-ene (DBU) (0.25mmol) was added in that order, and the reaction was stirred at 30 ℃ for 48 hours (TLC monitoring). Separating and purifying by column chromatography (petroleum ether: ethyl acetate: 8: 1-5: 1) to obtain the compound of the formula (14.2 mg), with a yield of 25%;

the preparation method 2 comprises the following steps: in a reaction tube, benzyl carbamate (0.1mmol of reactant concentration: 0.1mol/L) was dissolved in 1, 2-dichloroethane (1.0mL), and then α -chlorophenylethyl ketoxime (0.12mmol) and diisopropylethylamine (0.25mmol) were added in this order to the reaction mixture, and the reaction was stirred at 30 ℃ for 48 hours (TLC monitoring). Separating and purifying by column chromatography (petroleum ether: ethyl acetate: 8: 1-5: 1) to obtain the compound of the formula 28.8mg, with a yield of 51%;

the preparation method 3 comprises the following steps: in a 100mL round-bottom flask, benzyl carbamate (5.0mmol reactant concentration of 0.1mol/L) was dissolved in 1, 2-dichloroethane (50 mL); then, α -bromoacetophenone oxime (6.0mmol) and diisopropylethylamine (20mmol) were added in this order to the reaction mixture, and the reaction was stirred at 50 ℃ for 4 hours (TLC monitoring). Separating and purifying by column chromatography (petroleum ether: ethyl acetate: 8: 1-5: 1) to obtain the compound of the formula 1.12g, with a yield of 79%;

and (3) structural identification:¹HNMR(400MHz,CDCl₃) δ 7.63(d, J ═ 5.5Hz,2H),7.45(d, J ═ 7.5Hz,2H), 7.42-7.38 (m,4H), 7.37-7.33 (m,2H),5.34(s,2H),4.54(s,2H) are as shown in fig. 1;¹³CNMR(101MHz,CDCl₃) δ 156.1,135.1,134.9,130.0,129.1,128.8,128.7,128.4,126.0,125.2,77.5,77.2,76.8,68.8,48.0 is shown in fig. 2.

Based on the three preparation methods in example 1, it can be verified that the type of the added base and the reaction temperature can significantly affect the yield of the target product in the synthesis process of the 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride.

Example 2: preparation of the Compound of the formula

The preparation method comprises the following steps: in a reaction tube, benzyl carbamate (0.2mmol reactant concentration of 0.1mol/L) was dissolved in 1, 2-dichloroethane (2.0mL), and then a reaction mixture of α -bromo-p-fluoroacetophenone oxime (0.24mmol) and diisopropylethylamine (0.8mmol) was added in this order and the reaction was stirred at 50 ℃ for 4 hours (TLC monitoring). Separating and purifying by column chromatography (petroleum ether: ethyl acetate: 8: 1-5: 1) to obtain the compound of the formula (II a), 48.1mg, yield 80%;

and (3) structural identification:¹HNMR(300MHz,CDCl₃)δ7.63(dd,J＝8.7,5.5Hz,2H),7.49–7.42(m,2H),7.41–7.30(m,3H),7.11(t,J＝8.7Hz,2H),5.33(s,2H),4.52(s,2H)；¹³CNMR(75MHz,CDCl₃)δ163.0(d,J＝250.9Hz,1C),156.0,134.8,134.2,128.8,128.4,127.2(d,J＝8.3Hz,1C),122.3(d,J＝3.4Hz,1C),116.6(d,J＝22.3Hz,1C),68.8,48.0。

example 3: preparation of the Compound of the formula

The preparation method comprises the following steps: in a reaction tube, benzyl carbamate (0.2mmol reactant concentration of 0.1mol/L) was dissolved in 1, 2-dichloroethane (2.0mL), and then a reaction mixture of α -bromo-p-trifluoromethylacetophenone oxime (0.24mmol) and diisopropylethylamine (0.8mmol) was added in this order, and the reaction was stirred at 50 ℃ for 4 hours (TLC monitoring). Separating and purifying by column chromatography (petroleum ether: ethyl acetate: 8: 1-5: 1) to obtain compound III-c of the above formula (35.2 mg, yield 50%);

and (3) structural identification:¹HNMR(300MHz,DMSO-d₆)δ7.90–7.82(m,4H),7.48–7.42(m,2H),7.42–7.32(m,3H),5.28(s,2H),4.79(s,2H)；¹³CNMR(151MHz,DMSO-d₆)δ154.9,135.3,134.2,129.6,128.9(q,J＝32.0Hz,1C),128.5,128.4,128.2,126.0(q,J＝3.9Hz,1C),125.4,123.9(q,J＝272.0Hz,1C),67.8,48.8。

example 4: preparation of the Compound of the formula

The preparation method comprises the following steps: in a reaction tube, benzyl carbamate (0.2mmol reactant concentration of 0.1mol/L) was dissolved in 1, 2-dichloroethane (2.0mL), and then a reaction mixture of α -halogenometacyanoacetophenone oxime (0.24mmol) and diisopropylethylamine (0.8mmol) was added in this order, and the reaction was stirred at 50 ℃ for 4 hours (TLC monitoring). Separating and purifying by column chromatography (petroleum ether: ethyl acetate: 8: 1-5: 1) to obtain the compound of the formula (39.9 mg), with a yield of 65%;

and (3) structural identification:¹HNMR(600MHz,DMSO-d₆)δ8.07(s,1H),8.04(d,J＝9.6Hz,1H),7.87(d,J＝7.8Hz,1H),7.70(t,J＝7.9Hz,1H),7.48–7.44(m,2H),7.44–7.39(m,2H),7.39–7.34(m,1H),5.28(s,2H),4.76(s,2H)；¹³CNMR(151MHz,DMSO-d₆)δ154.9,135.3,133.6,132.6,130.3,128.9,128.5,128.4,128.2,128.1,127.0,118.9,112.7,67.8,48.8。

example 5: preparation of the Compound of the formula

The preparation method comprises the following steps: in a reaction tube, butyl carbamate (0.2mmol of reactant concentration: 0.1mol/L) was dissolved in 1, 2-dichloroethane (2.0mL), and then α -bromoacetophenone oxime (0.24mmol) and diisopropylethylamine (0.8mmol) were added in this order to the reaction mixture, and the reaction was stirred at 50 ℃ for 4 hours (TLC monitoring). Separating and purifying by column chromatography (petroleum ether: ethyl acetate: 8: 1-5: 1) to obtain the compound of the formula (32.3 mg) with a yield of 81%;

and (3) structural identification:¹HNMR(600MHz,DMSO-d₆) δ 7.69-7.65 (m,2H), 7.51-7.46 (m,2H), 7.45-7.40 (m,1H),4.70(s,2H),4.19(t, J ═ 6.5Hz,2H),1.62(dt, J ═ 15.3,6.6Hz,2H),1.38(H, J ═ 7.4Hz,2H),0.91(t, J ═ 7.4Hz,3H) are shown in fig. 3;¹³CNMR(151MHz,DMSO-d₆) δ 155.5,135.1,129.6,129.0,126.0,124.9,66.2,48.5,30.2,18.5,13.6 is shown in fig. 4.

Example 6: preparation of the Compound of the formula

The preparation method comprises the following steps: in a reaction tube, cyclopentyl carbamate (0.2mmol reactant concentration of 0.1mol/L) was dissolved in 1, 2-dichloroethane (2.0mL), and then a reaction mixture of α -bromoacetophenone oxime (0.24mmol) and diisopropylethylamine (0.8mmol) was added in this order, and the reaction was stirred at 50 ℃ for 4 hours (TLC monitoring). Separating and purifying by column chromatography (petroleum ether: ethyl acetate: 8: 1-5: 1) to obtain the compound of the formula (40.6 mg), with a yield of 78%;

and (3) structural identification:¹HNMR(600MHz,DMSO-d₆) δ 7.69-7.65 (m,2H), 7.51-7.47 (m,2H), 7.45-7.41 (m,1H),5.18(tt, J ═ 5.8,2.6Hz,1H),4.68(s,2H), 1.91-1.82 (m,2H), 1.79-1.72 (m,2H), 1.71-1.64 (m,2H), 1.62-1.53 (m,2H) are as shown in fig. 5;¹³CNMR(151MHz,DMSO-d₆) δ 155.2,135.0,129.6,129.0,126.0,124.8,79.7,48.5,32.2,23.2 is shown in fig. 6.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.