CN110818672B - Cyclobutenone compound with antioxidant effect and preparation method thereof - Google Patents
Cyclobutenone compound with antioxidant effect and preparation method thereof Download PDFInfo
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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Abstract
The invention discloses aA cyclobutenone compound with antioxidation and a preparation method thereof, belonging to the technical field of synthesis of functional organic molecules. The technical scheme provided by the invention has the key points that: the cyclobutenone compound has the structure
The invention is based on high competitive [2+2]]Cycloaddition reaction is carried out to obtain cyclobutenone compounds with novel structures, antioxidant detection is carried out by a DPPH method to find that target compounds have good antioxidant effect, and the compounds are expected to be applied to the fields of polyolefin material synthesis and the like and used as oxidants for inhibiting the polyolefin materials from oxidative degradation.
Description
Technical Field
The invention belongs to the technical field of functional organic molecule synthesis, and particularly relates to a cyclobutenone compound with an anti-oxidation effect and a preparation method thereof.
Background
The space charge distribution in the polymer affects the dielectric strength of the polymer. There are many factors that affect the space charge in the polymer, such as impurities introduced during the heat treatment preparation process received during the preparation of the sample, additives in the material, the structure and composition of the bulk material, oxidation of the material, the aggregation morphology, the interface state of the electrode and the sample, and the like. This not only presents difficulties in the characterization of the space charge of the polymer, but also provides many ways and solutions for engineering applications to increase or improve the dielectric strength of materials. Research shows that after the free radical scavenger is added into polyethylene, the free radical scavenger inhibits the generation of macromolecular free radicals and micromolecular products in the polyethylene electric aging process, so that the electric aging of the polyethylene is inhibited, traps causing space charge to reside in the polyethylene during the aging process are reduced, and the generation of space charge is reduced. Therefore, the development of a novel antioxidant free radical scavenger has great significance for the field of polyethylene synthesis.
Due to the special structural characteristics of the cyclobutenone derivative, the cyclobutenone derivative is widely applied to reaction intermediates in organic synthetic chemistry. For example, 4-acetoxyazetidinone is a key intermediate in penem and carbapenem antibiotics; the Moore group not only researches the four-electron electrocyclic ring-opening/6 re electrocyclic ring-closing reaction of a series of hydroxycyclobutenones, but also efficiently applies the reactions to the synthesis of various natural products, such as espinnol with antiparasitic effect, prostaglandin secretion inhibitor isoamidofrelone, lipoxygenase inhibitor lonapalene, precursor khellin of anti-atherosclerotic drugs and the like.
Therefore, the research on the synthesis method of cyclobutenone derivatives is also receiving more and more attention. Generally, the synthesis route of the compounds mainly utilizes ketene and acetylene compounds to carry out [2+2] cyclization reaction, or acetylene compounds and Fischer carbene compounds to carry out cyclization reaction. Although the method can effectively synthesize the cyclobutenone compound, the method cannot be widely applied to large-scale production due to the defects that a reaction substrate is not easy to synthesize, reaction raw materials have large limitations, the regioselectivity of the reaction is poor and the like. Therefore, there is a need to find a new method for synthesizing cyclobutenones simply and efficiently.
The invention not only synthesizes the cyclobutenone compound with a novel structure by a new method, but also discovers that the compound can eliminate free radicals by antioxidant research of a DPPH method, has good antioxidant effect, can be expected to be applied to the fields of cosmetic preparation, pharmaceutical production, plastic synthesis and the like, and can be used as an antioxidant additive for eliminating the free radicals.
Disclosure of Invention
The invention aims to provide a cyclobutenone compound with a novel structure and an antioxidant effect and a preparation method thereof.
The invention adopts the following technical scheme to solve the technical problems, and the cyclobutenone compound with the antioxidation function is characterized in that the compound has the following structure:
the invention adopts the following technical scheme for solving the technical problems, and the preparation method of the cyclobutenone compound with the antioxidation function is characterized by comprising the following specific steps of:
(1) carrying out competitive [2+2] cycloaddition reaction on 5-alkynyl-benzo [ d ] [1,3] dioxol and dibromoacetonitrile under the action of a catalyst to obtain 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromocyclobutene-2-one;
(2) 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromocyclobutene-2-one and Zn are subjected to oxidation addition and then to electrophilic reaction and hydrolysis by SE2 to obtain 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-bromocyclobutene-2-one;
(3) 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-bromocyclobutene-2-one and isoindoline-1, 3-dione are subjected to substitution reaction and then hydrolyzed to obtain 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-aminocyclobutene-2-one;
(4) and reacting the 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-aminocyclobutene-2-one with p-fluorophenylacetic acid to obtain the target compound.
Further limiting, the specific process of step (1) is as follows: adding a catalyst, trifluoromethanesulfonic anhydride and an alkaline compound into toluene in a reaction bottle with a water separator under the protection of nitrogen, heating and refluxing to remove water contained in a reaction system, then cooling to room temperature, adding dibromoacetonitrile, heating to reflux, further removing water in the reaction system, cooling to room temperature again, quickly adding 5-alkynyl-benzo [ d ] [1,3] dioxole under the protection of nitrogen, slowly heating to 70 ℃ under the protection of nitrogen, reacting for a period of time, adding water, continuously heating to reflux, adjusting the pH to 4-5 with 1N hydrochloric acid solution after the reaction is finished, extracting the reaction solution with ethyl acetate for multiple times, washing an organic layer with saturated sodium chloride solution for multiple times, drying anhydrous sodium sulfate, recovering the solvent under reduced pressure, purifying residues through column chromatography to obtain 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromocyclobuten-2-one; the catalyst is (triphenyl phosphine) gold chloride (I); the basic compound is 1, 8-bis-dimethylaminonaphthalene or 1, 8-diazabicycloundec-7-ene; the molar ratio of the 5-alkynyl-benzo [ d ] [1,3] dioxole to the catalyst to the charge amount of the trifluoromethanesulfonic anhydride to the charge amount of the basic compound to the charge amount of the dibromoacetonitrile is 1: 0.01-0.02: 1.2:1: 1.
Further limiting, the specific process of step (2) is as follows: adding zinc powder and iodine into a reaction solvent under the protection of nitrogen, adding a certain amount of water absorbent, slowly heating to reflux, keeping the nitrogen protection environment unchanged after reacting for a period of time, slowly cooling to 0 ℃, then slowly dropwise adding the same reaction solvent in which 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromocyclobutene-2-one is dissolved, slowly heating to 60 ℃ after dropwise adding, finding that the color of iodine disappears, filtering the reaction solution, starting vacuum to ensure that the filtrate can evaporate part of the reaction solvent at the temperature below 60 ℃ to prevent explosion, then slowly dropwise adding a toluene solution in which a certain amount of acetic acid is dissolved into the reaction solution in the environment of 0 ℃, keeping the temperature not more than 10 ℃, slowly heating to 50 ℃ after dropwise adding, after reacting for a period of time, pouring the reaction solution into water, extracting the reaction solution for multiple times by using dichloromethane, combining organic phases, and concentrating to obtain 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-bromocyclobutene-2-one; the reaction solvent is 1, 2-dibromoethane, tetrahydrofuran or diethyl ether; the water absorbent is bridged polyoxyethylene or bridged polyvinyl alcohol; the feeding amount molar ratio of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromocyclobutene-2-one to the zinc powder to the iodine is 1:2: 1; the mass ratio of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromocyclobutene-2-one to the water absorbent is 10: 1-3; the material charging quantity mass ratio of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromo cyclobutene-2-ketone to the acetic acid is 7: 10.
Further limiting, the specific process of step (3) is as follows: adding 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-bromocyclobutene-2-one and isoindoline-1, 3-dione into N, N-dimethylformamide, adding a ZSM-5 molecular sieve, stirring for a period of time under reflux, cooling, filtering the reaction solution, adding acetic acid into the reaction solution, heating to 80 ℃, reacting for a period of time, cooling to room temperature, adding a hydrochloric acid solution, continuously heating to 80 ℃, continuously stirring for a period of time, heating to room temperature, adjusting the pH of the reaction solution to 8-9 with ammonia water, filtering the reaction solution, removing a generated byproduct, namely benzoate, adding ethyl acetate into the filtrate, separating an organic phase, washing the organic phase with water and a saturated sodium chloride solution for multiple times, drying with anhydrous magnesium sulfate, and concentrating, separating by silica gel column chromatography to obtain 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-aminocyclobutene-2-one; the dosage of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-bromocyclobutene-2-one and the isoindoline-1, 3-dione is 1: 1; the mass ratio of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-bromocyclobutene-2-one to the ZSM-5 molecular sieve is 3: 1-2.
Further limiting, the specific process of step (4) is as follows: adding 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-aminocyclobutene-2-one and p-fluorobenzoic acid into N, N-dimethylformamide, adding a certain amount of potassium carbonate, stirring at room temperature for a period of time, cooling, washing an organic phase with water and a saturated sodium chloride solution for multiple times, drying with anhydrous magnesium sulfate, concentrating, and separating by silica gel column chromatography to obtain a target compound; the molar ratio of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-aminocyclobuten-2-one to p-fluorobenzoic acid to potassium carbonate is 1:1: 1.2.
The synthetic route of the cyclobutenone compound with the antioxidation function is as follows:
the invention has the following beneficial effects: 1, we find that competitive [2+2] cycloaddition reaction can easily occur between dibromoacetonitrile and 5-alkynyl-benzo [ d ] [1,3] dioxol, and we analyze that the existence of two electron-withdrawing bromine atoms increases the electron cloud density on C connected with the electron-withdrawing bromine atoms, so that electrophilic addition can easily occur with alkynyl, and the addition reaction between cyano and alkynyl is effectively avoided; 2. hydrolysis reaction is carried out during multi-step reaction post-treatment, the hydrolysis reaction treatment is relatively thorough, and byproducts are not easy to generate; 3. the target compound has a novel structure and good antioxidation.
Drawings
FIG. 1 nuclear magnetic hydrogen spectrum of the object compound
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
Adding 1g of (triphenylphosphine) gold chloride (I), 34g of trifluoromethanesulfonic anhydride and 21g of 1, 8-bis-dimethylaminonanaphthalene into 200mL of toluene in a reaction bottle with a water separator under the protection of nitrogen, slowly heating to reflux, removing water contained in a reaction system through the water separator, then cooling to room temperature, adding 20g of dibromoacetonitrile, heating to reflux again, further removing water in the reaction system, cooling to room temperature again, and rapidly adding 5-alkynyl-benzo [ d ] under the protection of nitrogen][1,3]15g of dioxole is added under the protection of nitrogen, and the temperature is slowly raised to 70 DEG CReacting for about 3 hours, adding 500mL of water into the reaction solution, continuously heating to reflux, continuously reacting for 5 hours, adjusting the pH to 4-5 by using 1N hydrochloric acid solution, extracting 100mL of the extraction reaction solution for multiple times by using ethyl acetate, combining organic layers, washing the organic layers for multiple times by using 100mL of saturated sodium chloride solution, drying the organic layers by using anhydrous sodium sulfate, recovering the solvent under reduced pressure, and purifying the residue by using column chromatography (eluent: V ethyl acetate: V petroleum ether ═ 1: 5) to obtain 3- (benzo [ d)][1.3]Dioxol-5-yl) -4, 4-dibromocyclobuten-2-one 30.4 g;1H NMR(400MHz,DMSO-d6):δ7.47(d,J＝4.0Hz,2H),6.93(d,J＝8.0Hz,1H),6.45(s,1H),4.34(s,2H).HR-MS(ESI+)m/z：346.9735[M+H]+。
example 2
Adding 0.5g of (triphenyl phosphorus) gold chloride (I), 34g of trifluoromethanesulfonic anhydride and 21g of 1, 8-bis-dimethylamino-naphthalene into 200mL of toluene in a reaction bottle with a water separator under the protection of nitrogen, slowly heating to reflux, removing water contained in a reaction system through the water separator, then cooling to room temperature, adding 20g of dibromoacetonitrile, heating to reflux again, further removing water in the reaction system, cooling to room temperature again, and rapidly adding 5-alkynyl-benzo [ d ] under the protection of nitrogen][1,3]Adding 15g of dioxole under the protection of nitrogen, slowly heating to 70 ℃, reacting for about 3h, adding 500mL of water into the reaction solution, continuously heating to reflux, continuously reacting for 5h, adjusting the pH to 4-5 with 1N hydrochloric acid solution, extracting 100mL of the extraction reaction solution for multiple times with ethyl acetate, combining organic layers, washing with 100mL of saturated sodium chloride solution for multiple times, drying with anhydrous sodium sulfate, recovering the solvent under reduced pressure, and purifying the residue by column chromatography (eluent: V ethyl acetate: V petroleum ether: 1: 5) to obtain 3- (benzo [ d ] benzene][1.3]Dioxol-5-yl) -4, 4-dibromocyclobuten-2-one 28.3 g;1H NMR(400MHz,DMSO-d6):δ7.47(d,J＝4.0Hz,2H),6.93(d,J＝8.0Hz,1H),6.45(s,1H),4.34(s,2H).HR-MS(ESI+)m/z：346.9735[M+H]+。
example 3
Adding 0.5g of (triphenyl phosphorus) gold chloride (I), 34g of trifluoromethanesulfonic anhydride and 15g of 1, 8-diazabicycloundec-7-ene into 200mL of toluene in a reaction bottle with a water separator under the protection of nitrogen, slowly heating to reflux, removing water contained in a reaction system through the water separator, then cooling to room temperature, adding 20g of dibromoacetonitrile, heating to reflux again, further removing water in the reaction system, cooling to room temperature again, and rapidly adding 5-alkynyl-benzo [ d ] under the protection of nitrogen][1,3]Adding 15g of dioxole under the protection of nitrogen, slowly heating to 70 ℃, reacting for about 3h, adding 500mL of water into the reaction solution, continuously heating to reflux, continuously reacting for 5h, adjusting the pH to 4-5 with 1N hydrochloric acid solution, extracting 100mL of the extraction reaction solution for multiple times with ethyl acetate, combining organic layers, washing with 100mL of saturated sodium chloride solution for multiple times, drying with anhydrous sodium sulfate, recovering the solvent under reduced pressure, and purifying the residue by column chromatography (eluent: V ethyl acetate: V petroleum ether: 1: 5) to obtain 3- (benzo [ d ] benzene][1.3]Dioxol-5-yl) -4, 4-dibromocyclobuten-2-one 18.5 g;1H NMR(400MHz,DMSO-d6):δ7.47(d,J＝4.0Hz,2H),6.93(d,J＝8.0Hz,1H),6.45(s,1H),4.34(s,2H).HR-MS(ESI+)m/z：346.9735[M+H]+。
example 4
Adding 13g of zinc powder and 25g of iodine into 300mL of 1, 2-dibromoethane in a reaction bottle under the protection of nitrogen, adding 10g of bridging polyoxyethylene, slowly heating to reflux, keeping the nitrogen protection environment unchanged after reacting for 1h, slowly cooling to 0 ℃, and then slowly dropwise adding the 3- (benzo [ d ] dissolved in the solution][1.3]35g of dioxol-5-yl) -4, 4-dibromocyclobutene-2-one in 500mL of 1, 2-dibromoethane, slowly heating to 60 ℃ after dropwise addition, filtering the reaction solution, turning onEvaporating 1, 2-dibromoethane from the filtrate at a temperature below 60 ℃ and the reaction temperature cannot exceed 60 ℃ to prevent explosion, evaporating 500mL of 1, 2-dibromoethane, slowly adding 300mL of toluene solution dissolved with 50g of acetic acid into the reaction solution in a 0 ℃ environment, keeping the temperature not to exceed 10 ℃, slowly heating to 50 ℃ after dropwise addition, reacting for 2h, pouring the reaction solution into water, extracting the reaction solution with dichloromethane for multiple times, combining organic phases, and concentrating to obtain the 3- (benzo [ d ] b][1.3]Dioxol-5-yl) -2-bromocyclobuten-2-one 22 g; HR-MS (ESI)+)m/z：268.0839[M+H]+。
Example 5
Adding 13g of zinc powder and 25g of iodine into 300mL of 1, 2-dibromoethane in a reaction flask under the protection of nitrogen, then adding 3.5g of bridging polyethylene oxide, slowly heating until the mixture flows back, keeping the nitrogen protection environment unchanged after reacting for 1h, slowly cooling to 0 ℃, and then slowly dropwise adding the mixture dissolved with 3- (benzo [ d ] benzene][1.3]After dropwise adding 500mL of 1, 2-dibromoethane solution of 35g of dioxol-5-yl) -4, 4-dibromocyclobutene-2-ketone, slowly heating to 60 ℃ to find that the color of iodine disappears, filtering the reaction solution, starting vacuum to evaporate 1, 2-dibromoethane from the filtrate at a temperature below 60 ℃, keeping the reaction temperature not higher than 60 ℃ to prevent explosion, evaporating 500mL of 1, 2-dibromoethane, then slowly adding 300mL of toluene solution dissolved with 50g of acetic acid into the reaction solution in a 0 ℃ environment, keeping the temperature not higher than 10 ℃, slowly heating to 50 ℃ after dropwise adding, reacting for 2 hours, pouring the reaction solution into water, extracting the reaction solution with dichloromethane for multiple times, combining organic phases, concentrating, and separating by silica gel column chromatography to obtain 3- (benzo [ d ] b][1.3]Dioxol-5-yl) -2-bromocyclobuten-2-one 13.5 g; HR-MS (ESI)+)m/z：268.0839[M+H]+。
Example 6
Adding 13g of zinc powder and 25g of iodine into 300mL of tetrahydrofuran in a reaction bottle under the protection of nitrogen, adding 10g of bridging polyoxyethylene, slowly heating to reflux, keeping the nitrogen protection environment unchanged after reacting for 1h, slowly cooling to 0 ℃, and then slowly dropwise adding the solution dissolved with 3- (benzo [ d ] in][1.3]Adding 500mL of 35g of tetrahydrofuran solution of dioxol-5-yl) -4, 4-dibromocyclobutene-2-one, slowly heating to 60 ℃ after dropwise adding, finding that the color of iodine disappears, filtering the reaction solution, starting vacuum to enable the filtrate to evaporate 1, 2-dibromoethane below 60 ℃, ensuring that the reaction temperature cannot exceed 60 ℃ to prevent explosion, evaporating 600mL of tetrahydrofuran, then slowly adding 300mL of toluene solution dissolved with 50g of acetic acid into the reaction solution in a 0 ℃ environment, keeping the temperature not to exceed 10 ℃, slowly heating to 50 ℃ after dropwise adding, reacting for 2 hours, pouring the reaction solution into water, extracting the reaction solution for multiple times by using dichloromethane, combining organic phases, and concentrating to obtain the 3- (benzo [ d ] b][1.3]Dioxol-5-yl) -2-bromocyclobuten-2-one 16.7 g; HR-MS (ESI)+)m/z：268.0839[M+H]+.
Example 7
Adding 13g of zinc powder and 25g of iodine into 300mL of ether in a reaction bottle under the protection of nitrogen, adding 10g of bridging polyoxyethylene, slowly heating to reflux, keeping the nitrogen protection environment unchanged after reacting for 1h, slowly cooling to 0 ℃, and then slowly dropwise adding the solution dissolved with 3- (benzo [ d ] b][1.3]Adding 500mL of 35g of diethyl ether solution of dioxol-5-yl) -4, 4-dibromocyclobutene-2-one, slowly heating to 60 ℃ after dropwise adding, finding that the color of iodine disappears, filtering the reaction solution, starting vacuum to enable the filtrate to evaporate 1, 2-dibromoethane below 60 ℃, the reaction temperature cannot exceed 60 ℃ to prevent explosion, evaporating 600mL of diethyl ether, then placing the reaction solution in an environment of 0 ℃, slowly adding 300mL of toluene solution dissolved with 50g of acetic acid into the reaction solution, keeping the temperature not to exceed 10 ℃, slowly heating to 50 ℃ after dropwise adding, reacting for 2h, pouring the reaction solution into water, extracting by using dichloromethane, and obtaining the productThe reaction solution is mixed for a plurality of times, and the organic phase is concentrated to obtain the 3- (benzo [ d ]][1.3]Dioxol-5-yl) -2-bromocyclobuten-2-one 14.1 g; HR-MS (ESI)+)m/z：268.0839[M+H]+.
Example 8
Adding 13g of zinc powder and 25g of iodine into 300mL of 1, 2-dibromoethane in a reaction bottle under the protection of nitrogen, adding 10g of bridging polyvinyl alcohol, slowly heating until the mixture flows back, keeping the nitrogen protection environment unchanged after reacting for 1h, slowly cooling to 0 ℃, and then slowly dropwise adding the mixture dissolved with 3- (benzo [ d ] benzene][1.3]After finishing dripping, slowly heating to 60 ℃ to find that the color of iodine disappears, filtering the reaction liquid, opening vacuum to ensure that the filtrate can evaporate 1, 2-dibromoethane below 60 ℃, the reaction temperature can not exceed 60 ℃ to prevent explosion, evaporating to remove 1, 2-dibromoethane 150mL, then, slowly dripping 500mL of toluene solution dissolved with 50g of acetic acid into the reaction liquid in an environment of 0 ℃, keeping the temperature not exceeding 10 ℃, after finishing dripping, slowly heating to 50 ℃, after reacting for 2 hours, pouring the reaction liquid into water, extracting the reaction liquid for multiple times by using dichloromethane, merging organic phases, and concentrating to obtain the 3- (benzo [ d ] benzene][1.3]13g of dioxol-5-yl) -2-bromocyclobuten-2-one; HR-MS (ESI)+)m/z：268.0839[M+H]+.
Example 9
In a reaction flask, 3- (benzo [ d ]][1.3]Adding 30g of dioxol-5-yl) -2-bromocyclobutene-2-one and 16g of isoindoline-1, 3-dione into 300mL of N, N-dimethylformamide, adding 10g of ZSM-5 molecular sieve, stirring for a period of time under reflux, cooling, filtering the reaction solution, adding 20g of acetic acid into the reaction solution, heating to 80 ℃, reacting for 1h, slowly cooling to room temperature, adding2N hydrochloric acid solution 200mL, continuously heating to 80 ℃, continuously stirring for reaction for 2h, slowly heating to room temperature, adjusting the pH of the reaction solution to 8-9 by using ammonia water, filtering the reaction solution, removing generated byproduct benzoate, adding 200mL of ethyl acetate into the filtrate, separating out an organic phase, washing the organic phase with water and saturated sodium chloride solution for multiple times, drying with anhydrous magnesium sulfate, concentrating, and separating by silica gel column chromatography to obtain 3- (benzo [ d ] d][1.3]Dioxol-5-yl) -2-aminocyclobuten-2-one 17.5 g;1H NMR(400MHz,DMSO-d6):δ9.13(s,2H),7.45(d,J＝4.0Hz,2H),7.01(d,J＝8.0Hz,1H),6.27(s,2H),3.85(s,2H).HR-MS(ESI+)m/z：204.1943[M+H]+.Anal.Calcd for C11H9NO3:C,65.02；H,4.46；N,6.89.Found:C,65.57；H,4.52；N,6.81。
example 10
In a reaction flask, 3- (benzo [ d ]][1.3]Adding 30g of dioxol-5-yl) -2-bromocyclobutene-2-one and 16g of isoindoline-1, 3-dione into 300mL of N, N-dimethylformamide, adding 20g of ZSM-5 molecular sieve, stirring for a period of time under a reflux state, cooling, filtering the reaction solution, adding 20g of acetic acid into the reaction solution, heating to 80 ℃, reacting for 1h, slowly cooling to room temperature, adding 200mL of 2N hydrochloric acid solution, continuously heating to 80 ℃, continuously stirring for reacting for 2h, slowly heating to room temperature, adjusting the pH of the reaction solution to 8-9 with ammonia water, filtering the reaction solution, removing the generated byproduct benzoate, adding 200mL of ethyl acetate into the filtrate, separating out an organic phase, washing the organic phase with water and saturated sodium chloride solution for multiple times, drying with anhydrous magnesium sulfate, concentrating, separating by silica gel column chromatography to obtain 3- (benzo [ d ]][1.3]Dioxol-5-yl) -2-aminocyclobuten-2-one 14.2 g;1H NMR(400MHz,DMSO-d6):δ9.13(s,2H),7.45(d,J＝4.0Hz,2H),7.01(d,J＝8.0Hz,1H),6.27(s,2H),3.85(s,2H).HR-MS(ESI+)m/z：204.1943[M+H]+.Anal.Calcd for C11H9NO3:C,65.02；H,4.46；N,6.89.Found:C,65.57；H,4.52；N,6.81。
example 11
In a reaction flask, 3- (benzo [ d ]][1.3]Adding 20g of dioxol-5-yl) -2-aminocyclobutene-2-one and 14g of p-fluorobenzoic acid into 200mL of N, N-dimethylformamide, adding 10g of potassium carbonate, stirring at room temperature for a period of time, cooling, washing an organic phase with water and a saturated sodium chloride solution for multiple times, drying with anhydrous magnesium sulfate, concentrating, and separating by silica gel column chromatography to obtain 28.7g of a target compound;1H NMR(400MHz,DMSO-d6):δ10.68(s,1H),7.89(d,J＝4.0Hz,2H),7.70(d,J＝4.0Hz,2H),7.52-7.39(m,2H),6.93(d,J＝8.0Hz,1H),6.11(s,2H),4.35(s,2H).HR-MS(ESI+)m/z：326.2981[M+H]+.Anal.Calcd for C18H12FNO4:C,66.46；H,3.72；N,4.31.Found:C,66.09；H,3.78；N,4.43。
example 12
DPPH method antioxidant Activity test
The preparation concentration is 2 multiplied by 10-4The concentration of the ethanol solution of DPPH is 1X 10-5mol/L、5×10- 5mol/L、10×10-5mol/L、15×10-5mol/L and 20X 10-5And (3) a mol/L antioxidant ethanol solution. After 5mL of the DPPH ethanol solution and 5mL of the antioxidant ethanol solution were mixed, the absorbance (A) at a wavelength of 517nm was measured by an ultraviolet-visible spectrophotometer. The antioxidant clearance (D) was calculated from the following equation.
D(％)＝[(ABlank space-AAntioxidant agent)/ABlank space]X 100; wherein: a. theBlank spaceIs the absorbance of the blank group added with the antioxidant; a. theAntioxidant agentAbsorbance for the test group to which antioxidant was added
| Concentration of target Compound (mol/L) | 1×10-5 | 5×10-5 | 10×10-5 | 15×10-5 | 20×10-5 |
| D(％) | 23.81 | 29.76 | 35.28 | 40.04 | 45.71 |
As can be seen from the table above, the antioxidant activity gradually increases with the increase of the concentration of the target compound, and the DPPH method antioxidant activity test can be used for detecting a free radical scavenger in polyethylene, so that the target compound is expected to become a free radical scavenger.
The foregoing embodiments illustrate the principles, principal features and advantages of the invention, and it will be understood by those skilled in the art that the invention is not limited to the foregoing embodiments, which are merely illustrative of the principles of the invention, and that various changes and modifications may be made therein without departing from the scope of the principles of the invention.
Claims (8)
1. A cyclobutenone compound with an antioxidant effect is characterized in that the molecular structure of the cyclobutenone compound is as follows:
2. a method for preparing the cyclobutenone compound of claim 1, which comprises the following steps:
(1) carrying out competitive [2+2] cycloaddition reaction on 5-alkynyl-benzo [ d ] [1,3] dioxol and dibromoacetonitrile under the action of a catalyst to obtain 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromocyclobutene-2-one;
(2) 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromocyclobutene-2-one and Zn are subjected to oxidation addition and then to electrophilic reaction and hydrolysis by SE2 to obtain 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-bromocyclobutene-2-one;
(3) 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-bromocyclobutene-2-one and isoindoline-1, 3-dione are subjected to substitution reaction and then hydrolyzed to obtain 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-aminocyclobutene-2-one;
(4) and reacting the 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-aminocyclobutene-2-one with p-fluorophenylacetic acid to obtain the target compound.
3. The preparation method of cyclobutenone compounds with antioxidant effect according to claim 2, wherein the specific process of the step (1) is as follows: adding a catalyst, trifluoromethanesulfonic anhydride and an alkaline compound into toluene in a reaction bottle with a water separator under the protection of nitrogen, heating and refluxing to remove water contained in a reaction system, then cooling to room temperature, adding dibromoacetonitrile, heating to reflux, further removing water in the reaction system, cooling to room temperature again, quickly adding 5-alkynyl-benzo [ d ] [1,3] dioxole under the protection of nitrogen, slowly heating to 70 ℃ under the protection of nitrogen, reacting for a period of time, adding water, continuously heating to reflux, adjusting the pH to 4-5 with 1N hydrochloric acid solution after the reaction is finished, extracting the reaction solution with ethyl acetate for multiple times, combining organic layers, washing with saturated sodium chloride solution for multiple times, drying with anhydrous sodium sulfate, recovering the solvent under reduced pressure, purifying the residue by column chromatography to obtain 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromocyclobuten-2-one; the catalyst is (triphenyl phosphine) gold chloride (I); the alkaline compound is 1, 8-bis-dimethylamino-naphthalene or 1, 8-diazabicycloundec-7-ene; the molar ratio of the 5-alkynyl-benzo [ d ] [1,3] dioxole to the catalyst to the feeding amount of the trifluoromethanesulfonic anhydride to the feeding amount of the basic compound to the feeding amount of the dibromoacetonitrile is 1: 0.01-0.02: 1.2:1: 1.
4. The method for preparing cyclobutenone compounds with antioxidant effect according to claim 2, wherein the specific process of the step (2) is as follows: adding zinc powder and iodine into a reaction solvent under the protection of nitrogen, adding a certain amount of water absorbent, slowly heating to reflux, keeping the nitrogen protection environment unchanged after reacting for a period of time, slowly cooling to 0 ℃, then slowly dropwise adding the same reaction solvent in which 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromocyclobutene-2-one is dissolved, slowly heating to 60 ℃ after dropwise adding, finding that the color of iodine disappears, filtering the reaction solution, starting vacuum to ensure that the filtrate can evaporate part of the reaction solvent at the temperature below 60 ℃ to prevent explosion, then placing in the environment of 0 ℃, slowly dropwise adding a toluene solution in which a certain amount of acetic acid is dissolved into the reaction solution, keeping the temperature not more than 10 ℃, slowly heating to 50 ℃ after dropwise adding, after reacting for a period of time, pouring the reaction solution into water, extracting the reaction solution with dichloromethane for multiple times, combining organic phases, and concentrating to obtain 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-bromocyclobutene-2-one; the reaction solvent is 1, 2-dibromoethane, tetrahydrofuran or diethyl ether; the water absorbent is bridged polyoxyethylene or bridged polyvinyl alcohol; the feeding amount molar ratio of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromo cyclobutene-2-one to the zinc powder to the iodine is 1:2: 1; the mass ratio of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromocyclobutene-2-one to the water absorbent is 10: 1-3; the mass ratio of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -4, 4-dibromocyclobutene-2-one to the acetic acid is 7: 10.
5. The method for preparing cyclobutenone compounds with antioxidant effect according to claim 2, wherein the specific process of the step (3) is as follows: adding 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-bromocyclobutene-2-one and isoindoline-1, 3-dione into N, N-dimethylformamide, adding a ZSM-5 molecular sieve, stirring for a period of time under reflux, cooling, filtering the reaction solution, adding acetic acid into the reaction solution, heating to 80 ℃, reacting for a period of time, cooling to room temperature, adding a hydrochloric acid solution, continuously heating to 80 ℃, continuously stirring for a period of time, heating to room temperature, adjusting the pH of the reaction solution to 8-9 with ammonia water, filtering the reaction solution, removing a generated byproduct, namely benzoate, adding ethyl acetate into the filtrate, separating an organic phase, washing the organic phase with water and a saturated sodium chloride solution for multiple times, drying with anhydrous magnesium sulfate, and concentrating, separating by silica gel column chromatography to obtain 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-aminocyclobutene-2-one; the dosage of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-bromocyclobutene-2-one and the isoindoline-1, 3-dione is 1: 1; the mass ratio of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-bromocyclobutene-2-one to the ZSM-5 molecular sieve is 3: 1-2.
6. The method for preparing cyclobutenone compounds with antioxidant effect according to claim 2, wherein the specific process of the step (4) is as follows: adding 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-aminocyclobuten-2-one and p-fluorobenzoic acid into N, N-dimethylformamide, adding a certain amount of alkaline compound, stirring at room temperature for a period of time, heating under vacuum, concentrating, adding an organic reagent or directly pouring into water to separate out a solid; after adding an organic reagent, washing an organic phase for multiple times by using water and a saturated sodium chloride solution, drying by using anhydrous magnesium sulfate, concentrating, and separating by using a silica gel column chromatography to obtain a target compound; the alkaline compound is potassium carbonate, potassium hydroxide or HATU and N, N-diisopropylethylamine; the feeding amount molar ratio of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-aminocyclobutene-2-one to the p-fluorobenzoic acid to the potassium carbonate is 1:1: 1.2; the mass ratio of the 3- (benzo [ d ] [1.3] dioxol-5-yl) -2-aminocyclobutene-2-one to HATU and N, N-diisopropylethylamine is 4:3: 3-4.
7. The method for preparing cyclobutenone compound with antioxidant effect according to claim 2, wherein the synthetic route of the cyclobutenone compound is as follows:
8. use of cyclobutenone compounds according to claim 1 for the preparation of radical scavengers.
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