CN113735773B - 2, 3-dihydro-1, 2-diazacyclobutene oxynitride and preparation method thereof - Google Patents
2, 3-dihydro-1, 2-diazacyclobutene oxynitride and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a 2, 3-dihydro-1, 2-diazacyclobutene oxynitride and a preparation method thereof, belonging to the field of organic synthesis, wherein the preparation method is directedαAdding organic solvent into the mixture of halogenated acetophenone oxime, carbamate and alkali, stirring at a certain temperature for reactionAfter 24 hours, separating and purifying to obtain the catalyst; the invention is realized by stepwise [3+1]]The cycloaddition reaction realizes the synthesis of 2, 3-dihydro-1, 2-diazacyclobutene oxynitride, and the compound can be used for constructing other series of heterocyclic compounds by taking the compound as a typical 1, 3-dipole for the 1, 3-dipole 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.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a 2, 3-dihydro-1, 2-diazacyclobutene oxynitride and a preparation method thereof.
Background
Nitrogen-containing quaternary heterocycles are widely used in clinical drugs and bioactive compounds, for example, beta-lactam antibiotics including cephalosporins, penicillins and the like all contain a beta-lactam core skeleton structure, and in addition, quaternary nitrogen-containing heterocycles can also be used as ligands in metal-catalyzed chemical transformations or as key intermediates for the synthesis of other nitrogen-containing heterocycles. Based on this, college construction of quaternary nitrogen-containing heterocycles has attracted increasing attention from chemists.
As a special nitrogen-containing heterocycle with high ring tension, the four-membered ring of 2, 3-dihydro-1, 2-diazacyclobutene nitrogen oxide contains two nitrogen atoms, and the synthesis of the compound still faces great challenges at present. The traditional method for synthesizing 2, 3-dihydro-1, 2-diazacyclobutene oxynitride is only reported as one example, and the method mainly uses the aziridine ring-expanding reaction, but the synthesis method has low yield and poor substrate adaptability.
So far, no further report exists on a method for synthesizing 2, 3-dihydro-1, 2-diazacyclobutene oxynitride with higher universality and efficiency, and based on the method, the development of an efficient synthesis method is necessary to construct the quaternary nitrogen heterocyclic skeleton.
Disclosure of Invention
One of the purposes of the invention is to provide a 2, 3-dihydro-1, 2-diazacyclobutene oxynitride compound which is a typical 1, 3-dipole and can be used for 1, 3-dipole cycloaddition reaction to construct other series of heterocyclic compounds.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: 2, 3-dihydro-1, 2-diazacyclobutene nitroxide having a structure represented by the following structural formula:
in the structural formula, R 1 The group is selected from one of aryl, heteroaryl and condensed aryl; r is R 2 The radicals are selected from aralkyl, straight-chain alkyl, branched-chain alkyl or cycloalkyl radicals as protecting groups.
As a preferable technical scheme: the R is 1 The 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 is 2 One selected from benzyl, propyl, isopropyl, butyl, isobutyl, hexyl, allyl, cyclopentyl, 2-chloroethyl, 2-trichloroethyl.
The invention provides a brand new 2, 3-dihydro-1, 2-diazacyclobutene oxynitride, which is a typical 1, 3-dipole and can be used for constructing other series of heterocyclic compounds through 1, 3-dipole cycloaddition reaction.
The second purpose of the invention is to provide the preparation method of the 2, 3-dihydro-1, 2-diazacyclobutene oxynitride, so as to solve the problems of low synthesis efficiency, poor substrate adaptation and the like in the traditional method for synthesizing the compound;
the preparation method can simply and conveniently synthesize the 2, 3-dihydro-1, 2-diazacyclobutene oxynitride. Lays a foundation for exploring the application of the compounds in the field of constructing other nitrogen-containing heterocycles.
The preparation method comprises sequentially weighing quantitative alpha-halogenated acetophenone oxime, carbamate and alkali, adding organic solvent into the mixture, reacting at a certain temperature for 2-48 hr, separating and purifying to obtain the final product
The reaction general formula is as follows:
the alpha-halogenated acetophenone oxime has the following structure:
wherein R is 1 The group is selected from aryl, heteroaryl, thick 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 is 2 The radicals are selected from aralkyl, straight-chain alkyl, branched-chain alkyl, cycloalkyl.
The preparation of 2, 3-dihydro-1, 2-diazacyclobutene oxynitride is realized through stepwise [3+1] cycloaddition reaction.
As a preferable 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, preferably 1, 2-dichloroethane. Because the reaction yield is highest under the solvent.
As a preferable technical scheme: the amount of the base used is at least 1.1 to 5.0 equivalents, preferably 4.0 equivalents. Experiments prove that the consumption of alkali is reduced, and the yield is reduced; the yield of the reaction was not further improved by increasing the amount of the base.
As a preferable technical scheme: the molar ratio of the alpha-halogenated acetophenone oxime to the carbamate is 1:1 to 4:1, preferably 2:1. Experiments prove that: when the molar ratio is 2:1, the reaction can obtain better results, namely the yield is highest, and the raw material consumption is saved. The reaction molar ratio is reduced, and the yield of the reaction is reduced; increasing the molar ratio of the reaction does not increase the reaction yield, but it wastes too much α -haloacetophenone oxime.
As a preferable technical scheme: the concentration of the carbamate is 0.05 to 0.4mol/L, preferably 0.10mol/L. The reaction is carried out at the concentration, and the reaction has higher yield under the condition of ensuring the precursor with less solvent consumption.
As a preferable technical scheme: the reaction temperature is 0 to 70 ℃, and more preferably the reaction temperature is 50 ℃. On the premise of ensuring better reaction yield, the reaction energy consumption is lower.
As a preferable technical scheme: the reaction time is 2 to 48 hours, preferably 4 hours.
The invention has the advantages that: the invention realizes the synthesis of 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride through the alkali-promoted stepwise [3+1] cycloaddition reaction, and the compound can be used for constructing other series of heterocyclic compounds by taking the compound as a typical 1, 3-dipole for the 1, 3-dipole cycloaddition reaction; 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 produced in example 1;
FIG. 2 is a carbon spectrum of the compound prepared in example 1;
FIG. 3 is a hydrogen spectrum of the compound prepared in example 5;
FIG. 4 is a carbon spectrum of the compound produced in example 5
FIG. 5 is a hydrogen spectrum of the compound produced in example 6;
FIG. 6 is a carbon spectrum of the compound produced in example 6.
Detailed Description
The invention will be further described with reference to the accompanying drawings.
Example 1: preparation of a Compound of the formula
The preparation method 1 comprises the following steps: benzyl carbamate (0.1 mmol reactant concentration of 0.1 mol/L) was dissolved in dichloromethane (1.0 mL) in the reaction tube, then α -bromoacetophenone oxime (0.12 mmol) was added sequentially, and the 1, 8-diazabicyclo undec-7-ene (DBU) (0.25 mmol) reaction mixture was stirred at 30deg.C 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 above formula, 14.2mg, yield 25%;
the preparation method 2 comprises the following steps: benzyl carbamate (0.1 mmol reactant concentration of 0.1 mol/L) was dissolved in 1, 2-dichloroethane (1.0 mL) and then α -chloroacetophenone oxime (0.12 mmol) was added sequentially and the diisopropylethylamine (0.25 mmol) reaction mixture 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 above formula, 28.8mg, yield 51%;
the preparation method comprises the following steps: benzyl carbamate (5.0 mmol reactant concentration 0.1 mol/L) was dissolved in 1, 2-dichloroethane (50 mL) in a 100mL round bottom flask; then, α -bromoacetophenone oxime (6.0 mmol) was added sequentially and the reaction mixture was stirred at 50℃for 4 hours (TLC monitoring) with diisopropylethylamine (20 mmol). Separating and purifying by column chromatography (petroleum ether: ethyl acetate=8:1-5:1) to obtain the compound of the above formula, 1.12g, yield 79%;
and (3) structural identification: 1 H NMR(400MHz,CDCl 3 ) Delta 7.63 (d, j=5.5 hz, 2H), 7.45 (d, j=7.5 hz, 2H), 7.42-7.38 (m, 4H), 7.37-7.33 (m, 2H), 5.34 (s, 2H), 4.54 (s, 2H) are shown in fig. 1; 13 C NMR(101MHz,CDCl 3 ) Delta 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 figure 2.
Based on the three preparation methods in the above example 1, it can be verified that the type and the reaction temperature of the added alkali can obviously influence the yield of the target product in the synthesis process of the 2, 3-dihydro-1, 2-diazacyclobutene oxynitride.
Example 2: preparation of a Compound of the formula
The preparation method comprises the following steps: benzyl carbamate (0.2 mmol reactant concentration 0.1 mol/L) was dissolved in 1, 2-dichloroethane (2.0 mL) and then α -bromo-p-fluoroacetophenone oxime (0.24 mmol) was added sequentially and the diisopropylethylamine (0.8 mmol) reaction mixture 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 above formula, 48.1mg, yield 80%;
and (3) structural identification: 1 H NMR(300MHz,CDCl 3 )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)； 13 C NMR(75MHz,CDCl 3 )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 a Compound of the formula
The preparation method comprises the following steps: benzyl carbamate (0.2 mmol reactant concentration 0.1 mol/L) was dissolved in 1, 2-dichloroethane (2.0 mL) and then α -bromo para-trifluoromethyl acetophenone oxime (0.24 mmol) was added sequentially and the diisopropylethylamine (0.8 mmol) reaction mixture 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 III-c with 35.2mg and 50% yield;
and (3) structural identification: 1 H NMR(300MHz,DMSO-d 6 )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)； 13 CNMR(151MHz,DMSO-d 6 )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 a Compound of the formula
The preparation method comprises the following steps: benzyl carbamate (0.2 mmol of reactant concentration 0.1 mol/L) was dissolved in 1, 2-dichloroethane (2.0 mL) and then α -halo-meta-cyanoacetophenone oxime (0.24 mmol) was added sequentially and the diisopropylethylamine (0.8 mmol) reaction mixture 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 above formula, 39.9mg, yield 65%;
and (3) structural identification: 1 H NMR(600MHz,DMSO-d 6 )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)； 13 C NMR(151MHz,DMSO-d 6 )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 a Compound of the formula
The preparation method comprises the following steps: in a reaction tube, butyl carbamate (0.2 mmol reactant concentration of 0.1 mol/L) was dissolved in 1, 2-dichloroethane (2.0 mL), then α -bromoacetophenone oxime (0.24 mmol) was added sequentially, and the diisopropylethylamine (0.8 mmol) reaction mixture 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 above formula, 32.3mg, yield 81%;
and (3) structural identification: 1 H NMR(600MHz,DMSO-d 6 )δ7.69–7.65(m,2H),7.51–7.46 (m, 2H), 7.45-7.40 (m, 1H), 4.70 (s, 2H), 4.19 (t, j=6.5 hz, 2H), 1.62 (dt, j=15.3, 6.6hz, 2H), 1.38 (H, j=7.4 hz, 2H), 0.91 (t, j=7.4 hz, 3H) are shown in fig. 3; 13 C NMR(151MHz,DMSO-d 6 ) Delta 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 a Compound of the formula
The preparation method comprises the following steps: in a reaction tube, cyclopentylcarbamate (0.2 mmol reactant concentration of 0.1 mol/L) was dissolved in 1, 2-dichloroethane (2.0 mL), and then α -bromoacetophenone oxime (0.24 mmol) was sequentially added thereto, and diisopropylethylamine (0.8 mmol) reaction mixture 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 above formula, 40.6mg, yield 78%;
and (3) structural identification: 1 H NMR(600MHz,DMSO-d 6 ) Delta 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; 13 C NMR(151MHz,DMSO-d 6 ) Delta 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 foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (8)
1. A preparation method of 2, 3-dihydro-1, 2-diazacyclobutene oxynitride is 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 complete, and then separation and purification are carried out, thus obtaining the preparation method;
the alpha-halogenated acetophenone oxime has the following structure
The carbamate has the following structure:
the 2, 3-dihydro-1, 2-diazacyclobutene oxynitride has the following structure:
in the structural formula, R is selected from bromo; r is R 1 The group is selected from phenyl or p-fluorophenyl or p-trifluoromethylphenyl or m-cyanophenyl; r is R 2 The group is selected from aralkyl, straight chain alkyl, branched alkyl or cycloalkyl;
the reaction temperature is 0-70 ℃, and the reaction time is 2-48 hours; the organic solvent is selected from one or more of dichloromethane, chloroform, 1, 2-dichloroethane, methyl tertiary butyl ether, toluene, methanol and acetonitrile; the molar ratio of the alpha-halogenated acetophenone oxime to the carbamate is 1:1-4:1; the concentration of the carbamate is 0.05-0.4 mol/L; the amount of the alkali is 1.1 to 5.0 equivalents.
2. The method of manufacturing according to claim 1, characterized in that: the organic solvent is 1, 2-dichloroethane.
3. The method of manufacturing according to claim 1, characterized in that: the base is diisopropylethylamine.
4. The method of manufacturing according to claim 1, characterized in that: the amount of base used was 4.0 equivalents.
5. The method of manufacturing according to claim 1, characterized in that: the molar ratio of the alpha-halogenated acetophenone oxime to the carbamate is 2:1.
6. The method of manufacturing according to claim 1, characterized in that: the concentration of the carbamate is 0.10mol/L.
7. The method of manufacturing according to claim 1, characterized in that: the reaction temperature was 50 ℃.
8. The method of manufacturing according to claim 1, characterized in that: the reaction time was 4 hours.
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