CN108383802A - A kind of mantoquita catalysis aryl aldehyde and nitromethane heterocyclic compound at 4- aryl -3- nitro isoxazoles method - Google Patents

A kind of mantoquita catalysis aryl aldehyde and nitromethane heterocyclic compound at 4- aryl -3- nitro isoxazoles method Download PDF

Info

Publication number
CN108383802A
CN108383802A CN201810370456.5A CN201810370456A CN108383802A CN 108383802 A CN108383802 A CN 108383802A CN 201810370456 A CN201810370456 A CN 201810370456A CN 108383802 A CN108383802 A CN 108383802A
Authority
CN
China
Prior art keywords
aryl
nitroisoxazole
nitromethane
aldehyde
aryl aldehyde
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201810370456.5A
Other languages
Chinese (zh)
Other versions
CN108383802B (en
Inventor
郭灿城
符美强
郭欣
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xinjiang Puhesu New Environmental Protection Materials Co ltd
Original Assignee
YUANJIANG HUALONG CATALYTIC TECHNOLOGY CO LTD
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by YUANJIANG HUALONG CATALYTIC TECHNOLOGY CO LTD filed Critical YUANJIANG HUALONG CATALYTIC TECHNOLOGY CO LTD
Priority to CN201810370456.5A priority Critical patent/CN108383802B/en
Publication of CN108383802A publication Critical patent/CN108383802A/en
Application granted granted Critical
Publication of CN108383802B publication Critical patent/CN108383802B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The invention discloses a kind of mantoquitas to be catalyzed the method for aryl aldehyde and nitromethane heterocyclic compound at 4 aryl, 3 nitro isoxazole, this method is in the organic solution system containing copper acetate and ammonium iodide, aryl aldehyde carries out heterocyclization with nitromethane, obtains 4 aryl, 3 nitro isoxazole；This method reaction condition is mild, and catalyst and raw material are cheap, and reaction yield is high, is conducive to industrialized production.

Description

Method for synthesizing 4-aryl-3-nitroisoxazole by catalyzing aryl aldehyde and nitromethane with copper salt
Technical Field
The invention relates to a synthetic method of an isoxazole derivative, in particular to a method for synthesizing 4-aryl-3-nitroisoxazole by catalyzing aryl aldehyde and nitromethane with copper salt, belonging to the field of synthesis of drug intermediates.
Background
Isoxazole derivatives have a heterocyclic structure, are very important compounds, and are widely used for organic synthesis, have a lot of biological activities, and also have very good pharmacological properties, such as certain effects on reducing blood sugar of human beings, eliminating pain of human beings, resisting inflammation of human beings, killing harmful bacteria, controlling and reducing harm of HIV, and the like.
The methods for synthesizing isoxazole derivatives, such as cyclization of ketoxime or hydroxylamine, 1,3-dipolar cycloaddition reaction, etc., are reported in many ways in the prior art, such as documents [ Kun Liu, Libo Xu, Joel P.Berger, Karen L.MacNaul, Gauchao Zhou, Thomas W.Dober, Michael J.Forrest, DavidE.Moller, and A.Brian J.Discovey of Novel Series of peroxisome promoter-derived Receptor α/gamma Dual ingredient for the purpose of the Type2 dyes, dye Synthesis, and Synthesis, 9.27, 5-reaction, 5-peptide J.1996, 5-peptide J.12, 5-heterocyclic, 5-2-chemical, 5-acetyl-D.A.5-9-D.A.A.A.Briant.Bioorg Med Chem 2007,15(7),2587-600.(d)Regine Riess,MichaelSabine Laschat,and VolkerEvaluation of protection group for 3-Hydroxyisoxazoles 2Short Access to 3-alkoxisoxazole-5-carbaldehyde and3-Hydroxyisoxazole-5-carbaldehyde, the pure Toxic Acid of Muscolite, Eur.J. Org.Chem.1998, 32479 (e) Tommy N.Johansen, Bjarke Ebert, PovlKroggaard-Larsen, and Lotte Brehm. Exceptivity Amino Acid derivatives, Resolution, Absolute hybridization, and Enantiology chemistry of2-Amino-3- (4-butyl-3-hydroxy-5-carbaldehyde. J. 1998, and J. about.41. about.J. about.51, 1998. For example, Manojit Palc et al [ R.Gangadhara Chary, G.Rajeshwar Reddy, Y.S.S.Ganesh, Manojit Palc, [ Effect of Aqueous Polyethylene Glycol on 1,3-Dipolar Cycloaddition of benzonitromethane/Ethyl 2-Nitroacetate with dipolarynohiles: Green Synthesis of Isoxazoles and Isoxazoles to terminal alkynes or alkenes via a 1:1 mixture of water-Polyethylene Glycol (PEG) was proposed, this method does not require the use of a catalyst and an organic solvent, and a comparative Green Synthesis method of isoxazole derivatives.
3-nitroisoxazole compounds are effective antibacterial agents, but introduction of nitro groups into isoxazole rings has difficulty, and no effective synthesis method is available at present. Nitromethane as "NO2"building blocks are widely used in organic synthesis methodologies, including the classical Henry reactions [ A) Zhong Lian, a Stig D. Frisia and TroelsSkrydstrup. Palladium-catalyst carbonylating α -aryl of Nitromethane. chem. Commun.,2015,51, 3600. 3603.(b) David A. Evans,. Daniel Seidel, Magnus Rueping, Hon Wai Lam, Jared T. Shaw, and C.Wadowney.A New Coppermacetate-bis (oxazoline) -catalyst, Enantioselective Henry reaction.AM. CHEM. SOC.2003,125,12692-12693, (c) James D.white and SubrataShaw.A. New Catalyst for the asymmetry Reaction, Synthesis of β -Nitroethane in High energy aromatic Processes Org.Lett, Vol.14, No.24,2012,6270 20156273, (d) Li, Y., Huang, Y., Gui, Y., Sun, J., Li, J.J., Zha, Z.; Wang, Z., Copper-Catalyst aromatic selection HenReaction of a, gamma-Unsaturated alpha-ketones, sodium, naphthalene, ethylene.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a novel method for synthesizing 4-aryl-3-nitroisoxazole by catalyzing aryl aldehyde and nitromethane with copper salt, which has the advantages of mild reaction conditions, cheap catalyst and raw materials, high reaction yield and contribution to industrial production.
In order to realize the technical purpose, the invention provides a method for synthesizing 4-aryl-3-nitroisoxazole by heterocyclic ring of aryl aldehyde and nitromethane under the catalysis of copper salt, which comprises the following steps of carrying out heterocyclic ring reaction on the aryl aldehyde and the nitromethane in an organic solution system containing copper acetate and ammonium iodide to obtain 4-aryl-3-nitroisoxazole;
the aryl aldehyde has the structure of formula 1:
the 4-aryl-3-nitroisoxazole has a structure of formula 2:
wherein,
ar is aryl.
In a preferred embodiment, the aryl group is phenyl, substituted phenyl, naphthyl or substituted naphthyl. Preferred substituted phenyl groups include halogen-substituted phenyl groups (e.g., fluorine, chlorine, bromine, iodine, etc., and the number of substituents may be 1 to 5), alkyl-substituted phenyl groups (e.g., C)1～C5The lower alkyl group of (1) is preferably non-ortho-substituted with 1 to 3 substituents, and alkoxy-substituted phenyl (e.g., C)1～C5The alkoxy group of (1) is preferably non-ortho-substituted with 1 to 3 substituents, cyano-substituted phenyl (1 to 2 substituents), nitro-substituted phenyl (1 to 2 substituents), trifluoromethyl-substituted phenyl (1 to 2 substituents) or hydroxy-substituted phenyl (1 to 2 substituents being non-ortho-substituted with 1 to 2 substituents). More preferred substituted phenyl groups are 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 3-chlorophenyl, 3-methylphenyl, 3-nitrophenyl, 3-hydroxyphenyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl or 2-nitrophenyl. Preferred naphthyl groups having substituents are halogen-substituted naphthyl groups (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl-substituted naphthyl groups (e.g., C)1～C5Lower alkyl of (2), alkoxy-substituted naphthyl (e.g. C)1～C5Alkoxy) cyano-substituted naphthyl, nitro-substituted naphthyl, trifluoromethyl-substituted naphthyl or hydroxy-substituted naphthyl, which are suitable in principle for the invention, and are not described in detail here, since these starting materials are relatively uncommon and expensive.
Preferably, the organic solution system comprises DMSO and/or methanol solvent. Most preferred is methanol.
Preferably, the addition amount of the copper acetate is 30-80% of the molar amount of the aryl aldehyde. Generally, the addition amount of copper acetate is 50% of the molar amount of aryl aldehyde, so that a better reaction effect can be achieved.
Preferably, the addition amount of the ammonium iodide is 50 to 150% of the molar amount of the aryl aldehyde. The preferred ratio is such that the amount of ammonium iodide added is 100% of the molar amount of the arylaldehyde.
Preferably, the addition amount of the nitromethane is 10-40 times of the molar weight of the aryl aldehyde compound. The reaction ratio of the two is nitromethane: the aldehyde compound is 2:1, and the conversion efficiency of the aldehyde compound can be improved by excessive nitromethane.
In a preferable scheme, the reaction temperature of the cyclization reaction is preferably 50-70 ℃, and the reaction time is 22-28 h.
In a preferred embodiment, the reaction can be carried out in air or under a protective atmosphere.
The synthetic route of the 4-aryl-3-nitroisoxazole synthesized by catalyzing aryl aldehyde and nitromethane with the copper salt is as follows:
the invention further provides a reaction principle of aryl aldehyde and nitromethane heterocycle. The following four-step reactions (1) to (3) are designed to illustrate the reasonable mechanism of the heterocyclic reaction. Taking 4-chlorobenzaldehyde 1b and nitromethane as an example, in the cyclization reaction process, a target product 2b and a henry reaction product C are simultaneously separated from a reaction liquid, and in order to verify that the henry reaction product C is a byproduct or an intermediate product, the henry reaction product C is adopted as a reaction raw material to replace 4-chlorobenzaldehyde 1b to continue reacting with nitromethane, and surprisingly, the henry reaction product C is converted into the target product 2b, which indicates that the henry reaction product C is a key intermediate for cyclization reaction of aryl aldehydes and nitromethane. In addition, we have employed deuterated nitroformazansThe target product (2 b-d) is found by performing an experiment by replacing nitromethane with alkane1) In which deuterium is included. Thus, it was confirmed that nitromethane participates in the cyclization.
Combining the above experimental results with the existing theoretical knowledge base, the following reasonable mechanism can be proposed (taking the reaction of 4-chlorobenzaldehyde and nitromethane as an example for illustration): firstly, 4-chlorphenyl formaldehyde and one molecule of nitromethane are subjected to Henry reaction to generate a 1- (4-chlorphenyl) -2-nitroethylene intermediate C, the intermediate C is captured by free nitromethane negative ions to form a double nitro compound E, and NO is generated due to the double nitro compound E2The strong electron-pulling effect of the method leads the carbon atom connected with the nitro group to be positively charged, so that the dinitro compound E is easily cyclized into an intermediate F, the intermediate F is unstable, the carbon-carbon bond is easily cracked, the nitrogen-oxygen bond (path 1 or path 2 may exist) is attacked, the intermediate G of the nitrogen oxide heterocyclic compound is generated by recombination and cyclization, the intermediate G is subjected to elimination reaction to remove small molecular water, and the target product 2b is obtained.
Compared with the prior art, the technical scheme of the invention has the beneficial technical effects that:
1) the invention firstly adopts aryl aldehyde and nitromethane as raw materials to synthesize 4-aryl-3-nitroisoxazole by one-step heterocyclic ring, and provides a new effective synthetic approach for 3-nitroisoxazole compound antibacterial agents;
2) the method for synthesizing the 4-aryl-3-nitroisoxazole adopts copper acetate as a catalyst, and the copper acetate catalyst is relatively cheap, so that the synthesis cost of the 4-aryl-3-nitroisoxazole is reduced;
3) the method for synthesizing the 4-aryl-3-nitroisoxazole is completed by one step through a one-pot method, and is simple to operate;
4) the method for synthesizing the 4-aryl-3-nitroisoxazole has mild reaction conditions, can complete the reaction at a lower temperature, and has higher reaction yield.
Drawings
FIG. 1 is a 1H NMR spectrum of 4-aryl-3-nitroisoxazole in example 1;
FIG. 2 is a 13C NMR spectrum of 4-aryl-3-nitroisoxazole in example 1;
FIG. 3 is a 1H NMR spectrum of 4-aryl-3-nitroisoxazole in example 9;
FIG. 4 is a 13C NMR spectrum of 4-aryl-3-nitroisoxazole in example 9;
FIG. 5 is a 1H NMR spectrum of 4-aryl-3-nitroisoxazole in example 11;
FIG. 6 is a 13C NMR spectrum of 4-aryl-3-nitroisoxazole in example 11.
Detailed Description
The following examples are intended to further illustrate the present disclosure, but not to limit the scope of the claims.
All reactions were performed in Schlenk tubes unless otherwise noted.
All reaction starting solvents were obtained from commercial sources and used without further purification.
The product is separated by silica gel chromatographic column and silica gel (granularity is 300-400 meshes).
1H NMR (400MHz), 13C NMR (100MHz) and 19F NMR (376MHz) measurements were performed using a Bruker ADVANCEEIII spectrometer with CDCl3As solvent, TMS as internal standard, chemical shift in parts per million(ppm) is referred to as 0.0ppm of tetramethylsilane. The following abbreviations (or combinations thereof) are used to explain the multiplicity: s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad. Coupling constant J is in Hertz (Hz). Chemical shifts are expressed in ppm, with the center line for the triplet state referenced to deuterated chloroform at 77.0ppm or the center line for the heptad state referenced to deuterated DMSO at 39.52 ppm.
The GC-MS adopts a GC-MS QP2010 device for detection, the HRMS adopts an Electron Ionization (EI) method for measurement, the type of the mass analyzer is TOF, and the EI is detected by an Esquire 3000plus instrument.
Condition optimization experiment:
to find the best reaction, first, Cu (OAc)2P-chlorobenzaldehyde as a catalyst reacts with nitromethane in methanol at 40 ℃ for 24h under an air atmosphere. Without additives (Table 1, entry 1) or when k is used2CO3When (Table 1, entry 2), traces of the desired product isoxazole 2a were observed. When potassium iodide is used as an additive, the yield of the target product isoxazole 2a is improved, and when NH is used4When I is used as an additive, the yield of the target product isoxazole 2a reaches 24 percent (Table 1, entries 3-4), which shows that the introduction of ammonium iodide has obvious promotion effect on the reaction. As for the optimization of the reaction solvent, by trying a large amount of solvents, it was found that the reaction in alcohol and DMSO solvents gave a yield of the desired product isoxazole 2a, and the best solvent was found to be methanol (Table 1, entry 4) in a significantly higher yield than ethanol (Table 1, entry 5) or DMSO (entry 7 in Table 1) and the like. The reaction temperature also has an influence on the yield of the desired isoxazole 2 a. The corresponding isoxazole 2a, the target product, is obtained in 35% yield when the temperature is raised to 60 ℃ (Table 1, entry 8). Further raising the temperature to 80 ℃ did not increase the target product isoxazole 2a (Table 1, item 9), indicating that the reaction proceeded smoothly at a temperature in the range of 40-80 ℃, but 60 ℃ was a more preferable reaction condition. Furthermore, by extending the time of the chemical reaction to 28 hours (table 1, entries 10-11), the yield can be increased to 55%. The catalyst is also optimized and screened as vinegarNo product was detected when zinc or copper chloride replaced the catalyst copper acetate (Table 1, entries 12-13), demonstrating that copper acetate served an irreplaceable role in the reaction.
Substrate screening experiments:
the range of aryl aldehyde is expanded to the synthesis of various 4-aryl-3-nitroisoxazole derivatives through optimized reaction conditions. As shown in table 2 below, a wide variety of aryl aldehyde derivatives such as Cl (2a) and Br (2b) in the para position are suitable for use in the present scheme and the corresponding products are obtained in good yields. Having electron-neutral groups such as H (2c) or Me (2d), electron-rich groups such as OMe (2e) and electron-poor groups such as CN (2g), NO2(2h) Or CF3(2i) The yield obtained by the substrate family of (1) is up to 67%. However, the benzene ring is para-substituted for NMe2(2f) CHO (2j) or COOH (2k) gave only a Henry reaction product, and did not give 4-aryl-3-nitroisoxazole. Electron donating groups or electron withdrawing groups (2l to 2o) substituted on the 3-position of the aromatic ring have slightly reduced reactivity. Meanwhile, the reaction effect is good for most of the aldehyde (2 p-2 s) with ortho-substituted benzene ring. A notable exception is salicylaldehyde (2t), which does not give the desired target 4-aryl-3-nitroisoxazole. Unfortunately, the desired isoxazole derivative product was not observed when 2,4, 6-trimethylbenzaldehyde was used as substrate (2 u). Extensive screening revealed that aldehydes having a naphthyl group also showed good reactivity to the heterocyclic product (2 v).
In addition, the range of aldehydes other than benzene rings was further examined as shown in table 3. However, 4-pyridinecarboxaldehyde (3a) failed to produce good results. However, under the current conditions, the reaction of formamide with alkylaldehydes (3b, 3c) is slow, which may be due to electron conjugation effects.
The following examples further illustrate the reaction results of various substrates under preferred reaction conditions after optimal reaction conditions and reactions are preferred, and all of the following examples are conducted as follows, and the amount of nitromethane used is increased in the following examples in order to obtain higher conversion of aldehyde compounds.
In a 25mL Schlenk tube, Cu (OAc)2·H2O(0.25mmol，50.0mol％)，NH4I (0.5mmol, 1.0 equiv.) and aryl aldehyde (0.5mmol, 1.0 equiv.) are dissolved in CH3OH (2 mL). CH was then added via syringe3NO2(10mmol, 20 equiv.). The mixture was stirred at 60 ℃ for 28 hours in air. After the reaction is finished, cooling the obtained solution to room temperature; the solution was diluted with ethyl acetate (10mL), washed with water (5mL), extracted with ethyl acetate (3X 5mL), and washed with anhydrous Na2SO4And (5) drying. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether) to give the desired product.
Example 1
Aryl aldehyde: 4-chlorobenzaldehyde;
4-aryl-3-nitroisoxazole:
white solid product, yield 55%.
1H NMR(400MHz,CDCl3)δ8.65(s,1H),7.45(d,J＝7.6Hz,2H),7.35(d,J＝7.5Hz,2H)；
13C NMR(101MHz,CDCl3)δ160.03(s),135.94(s),130.32(s),129.26(s),122.92(s),115.98(s)；
HRMS(EI):calculated for C9H5N2O3Cl:223.9983；found:223.9982。
Example 2
Aryl aldehyde: 4-bromobenzaldehyde;
4-aryl-3-nitroisoxazole:
a yellow solid product; the yield was 71%.
1H NMR(400MHz,CDCl3)δ8.66(s,1H),7.59(d,J＝8.0Hz,2H),7.28(d,J＝8.2Hz,2H)；
13C NMR(101MHz,CDCl3)δ160.07(s),132.14(s),130.52(s),124.04(s),123.37(s),115.97(s)；
HRMS(EI):calculated for C9H5N2O3Br:267.9484；found:267.9488。
Example 3
Aryl aldehyde: benzaldehyde;
4-aryl-3-nitroisoxazole:
a light yellow oil, yield 67%.
1H NMR(400MHz,CDCl3)δ8.63(s,1H),7.47(d,J＝2.3Hz,3H),7.40(d,J＝2.0Hz,2H)；
13C NMR(101MHz,CDCl3)δ159.82(s),129.61(s),128.93(d,J＝7.6Hz),124.46(s),116.91(s)；
HRMS(EI):calculated for C9H6N2O3:190.0378；found:1900377。
Example 4
Aryl aldehyde: 4-methylbenzaldehyde;
4-aryl-3-nitroisoxazole:
yellow oil, 56% yield.
1H NMR(400MHz,CDCl3)δ8.59(s,1H),7.31–7.22(m,4H),2.40(s,3H)；
13C NMR(101MHz,CDCl3)δ159.67(s),139.71(s),129.60(s),128.66(s),121.36(s),116.79(s),21.21(s)；
HRMS(EI):calculated for C10H8N2O3:204.0535；found:204.0531。
Example 5
Aryl aldehyde: 4-cyanobenzaldehyde;
4-aryl-3-nitroisoxazole:
product as a yellow solid in 42% yield.
1H NMR(400MHz,CDCl3)δ8.74(s,1H),7.78(d,J＝7.7Hz,2H),7.55(d,J＝7.6Hz,2H)；
13C NMR(101MHz,CDCl3)δ160.56(s),132.65(s),129.83(s),129.29(s),117.86(s),113.67(s)；
HRMS(EI):calculated for C10H5N3O3:215.0331；found:215.0337。
Example 6
Aryl aldehyde: 4-nitrobenzaldehyde;
4-aryl-3-nitroisoxazole:
white solid, yield 37%.
1H NMR(400MHz,CDCl3)δ8.82(s,1H),8.33(d,J＝7.5Hz,2H),7.64(d,J＝7.4Hz,2H)；
13C NMR(101MHz,CDCl3)δ160.84(s),148.36(s),131.13(s),130.18(s),124.04(s),115.24(s)；
HRMS(EI):calculated for C9H5N3O5:235.0229；found:235.0233。
Example 7
Aryl aldehyde: 4-trifluoromethylbenzaldehyde;
4-aryl-3-nitroisoxazole:
pale yellow liquid, yield 56%.
1H NMR(400MHz,CDCl3)δ8.74(s,1H),7.74(d,J＝7.8Hz,2H),7.56(d,J＝7.8Hz,2H)；
13C NMR(101MHz,CDCl3)δ160.60(s),132.09(s),131.76(s),131.43(s),131.11(s),130.40(s),129.51(s),128.30(s),127.70(s),125.90(s),125.87(s),125.83(s),125.79(s),125.00(s),122.29(s),119.58(s),115.82(s)；
HRMS(EI):calculated for C10H5N2O3F3:258.0252；found:258.0253。
Example 8
Aryl aldehyde: 3-chlorobenzaldehyde;
4-aryl-3-nitroisoxazole:
white oil, yield 37%.
1H NMR(400MHz,CDCl3)δ8.70(s,1H),7.41(q,J＝8.8Hz,3H),7.30(d,J＝7.3Hz,1H)；
13C NMR(101MHz,CDCl3)δ160.44(s),134.61(s),130.10(s),129.61(s),128.91(s),127.17(s),126.12(s),115.59(s),77.32(s),77.00(s),76.68(s)；
HRMS(EI):calculated for C9H5N2O3Cl:223.9989；found:223.0991。
Example 9
Aryl aldehyde: 3-methylbenzaldehyde;
4-aryl-3-nitroisoxazole:
pale yellow oil, 39% yield.
1H NMR(400MHz,CDCl3)δ8.60(s,1H),7.34(t,J＝7.4Hz,1H),7.28(s,1H),7.18(d,J＝7.9Hz,2H),2.39(s,3H)；
13C NMR(101MHz,CDCl3)δ159.76(s),138.80(s),130.33(s),129.41(s),128.82(s),125.87(s),124.28(s),116.92(s),21.27(s)；
HRMS(EI):calculated for C10H8N2O3:204.0535；found:204.0532。
Example 10
Aryl aldehyde: 3-nitrobenzaldehyde;
4-aryl-3-nitroisoxazole:
white oil, yield 36%.
1H NMR(400MHz,CDCl3)δ8.84(s,1H),8.33(d,J＝12.8Hz,2H),7.80(d,J＝7.5Hz,1H),7.71(t,J＝7.7Hz,1H)；
13C NMR(101MHz,CDCl3)δ161.02(s),148.24(s),135.18(s),130.07(s),126.34(s),124.40(s),124.20(s),115.09(s)；
HRMS(EI):calculated for C9H5N3O5:235.0229；found:235.0233。
Example 11
Aryl aldehyde: 2-fluorobenzaldehyde;
4-aryl-3-nitroisoxazole:
yellow oil, 76% yield.
1H NMR(400MHz,CDCl3)δ8.71(s,1H),7.47(dd,J＝13.4,7.3Hz,1H),7.38(t,J＝7.4Hz,1H),7.25(d,J＝7.3Hz,1H),7.19(t,J＝9.2Hz,1H)；
13C NMR(101MHz,CDCl3)δ160.95(s),160.72(s),160.69(s),158.48(s),131.74(s),131.66(s),130.41(s),130.39(s),124.67(s),124.64(s),116.12(s),115.91(s),112.86(s),112.71(s),110.65(s)；
HRMS(EI):calculated for C9H5N2O3F:208.0284；found:208.0283。
Example 12
Aryl aldehyde: 2-chlorobenzaldehyde;
4-aryl-3-nitroisoxazole:
a pale yellow oil, yield 57%.
1H NMR(400MHz,CDCl3)δ8.66(s,1H),7.51(d,J＝7.7Hz,1H),7.43(dd,J＝7.7,5.6Hz,1H),7.37(d,J＝2.4Hz,2H)；
13C NMR(101MHz,CDCl3)δ161.01(s),134.01(s),131.26(s),131.06(s),129.86(s),127.14(s),124.03(s),114.10(s)；
HRMS(EI):calculated for C9H5N2O3Cl:223.9989；found:223.9988。
Example 13
Aryl aldehyde: 2-bromobenzaldehyde;
4-aryl-3-nitroisoxazole:
yellow oil, 56% yield.
1H NMR(400MHz,CDCl3)δ8.66(s,1H),8.30(d,J＝8.0Hz,1H),7.75(dt,J＝15.5,7.5Hz,2H),7.48(d,J＝7.3Hz,1H)；
13C NMR(101MHz,CDCl3)δ160.98(s),133.10(s),131.45(s),131.20(s),127.69(s),126.21(s),124.23(s),115.90(s)；
HRMS(EI):calculated for C9H5N2O3Br:267.9484；found:267.9480。
Example 14
Aryl aldehyde: 2-nitrobenzaldehyde;
4-aryl-3-nitroisoxazole:
a pale yellow oil, yield 54%.
1H NMR(400MHz,CDCl3)δ8.66(s,1H),8.30(d,J＝8.0Hz,1H),7.75(dt,J＝15.5,7.5Hz,2H)；
13C NMR(101MHz,CDCl3)δ160.01(s),134.10(s),132.74(s),131.10(s),125.96(s),125.68(s),120.55(s),114.36(s)；
HRMS(EI):calculated for C9H5N3O5:235.0229；found:235.0230。

Claims (9)

1. A method for synthesizing 4-aryl-3-nitroisoxazole by catalyzing aryl aldehyde and nitromethane with copper salt is characterized by comprising the following steps: in an organic solution system containing copper acetate and ammonium iodide, aryl aldehyde and nitromethane carry out heterocyclic reaction to obtain 4-aryl-3-nitroisoxazole;
the aryl aldehyde has the structure of formula 1:
the 4-aryl-3-nitroisoxazole has a structure of formula 2:
wherein,
ar is aryl.
2. The method for heterocyclic synthesis of 4-aryl-3-nitroisoxazole from aryl aldehyde and nitromethane under catalysis of copper salt according to claim 1, characterized in that:
the aryl is phenyl, phenyl containing substituent, naphthyl or naphthyl containing substituent.
3. The method for synthesizing 4-aryl-3-nitroisoxazole by heterocyclic ring of aryl aldehyde and nitromethane under catalysis of copper salt according to claim 2, characterized in that:
the phenyl containing the substituent is halogen substituted phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, cyano substituted phenyl, nitro substituted phenyl, trifluoromethyl substituted phenyl or hydroxyl substituted phenyl;
the naphthyl containing the substituent group is halogen substituted naphthyl, alkyl substituted naphthyl, alkoxy substituted naphthyl, cyano substituted naphthyl, nitro substituted naphthyl, trifluoromethyl substituted naphthyl or hydroxyl substituted naphthyl.
4. The method for heterocyclic synthesis of 4-aryl-3-nitroisoxazole from aryl aldehyde and nitromethane under catalysis of copper salt according to claim 3, characterized in that:
the phenyl containing the substituent is 4-chlorphenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 3-chlorphenyl, 3-methylphenyl, 3-nitrophenyl, 3-hydroxyphenyl, 2-chlorphenyl, 2-fluorophenyl, 2-bromophenyl or 2-nitrophenyl.
5. The method for heterocyclic synthesis of 4-aryl-3-nitroisoxazole from aryl aldehyde and nitromethane under catalysis of copper salt according to claim 1, characterized in that: the organic solution system comprises DMSO and/or methanol solvent.
6. The method for synthesizing 4-aryl-3-nitroisoxazole through heterocyclic ring of aryl aldehyde and nitromethane under catalysis of copper salt according to any one of claims 1 to 5, characterized in that:
the addition amount of the copper acetate is 30-80% of the molar amount of the aryl aldehyde.
7. The method for synthesizing 4-aryl-3-nitroisoxazole through heterocyclic ring of aryl aldehyde and nitromethane under catalysis of copper salt according to any one of claims 1 to 5, characterized in that:
the addition amount of the ammonium iodide is 50-150% of the molar amount of the aryl aldehyde.
8. The method for synthesizing 4-aryl-3-nitroisoxazole through heterocyclic ring of aryl aldehyde and nitromethane under catalysis of copper salt according to any one of claims 1 to 5, characterized in that:
the addition amount of the nitromethane is 10-40 times of the molar weight of the aryl aldehyde.
9. The method for synthesizing 4-aryl-3-nitroisoxazole through heterocyclic ring of aryl aldehyde and nitromethane under catalysis of copper salt according to any one of claims 1 to 5, characterized in that: the reaction temperature of the cyclization reaction is 50-70 ℃, and the reaction time is 22-28 h.
CN201810370456.5A 2018-04-24 2018-04-24 Method for synthesizing 4-aryl-3-nitroisoxazole by catalyzing aryl aldehyde and nitromethane with copper salt Active CN108383802B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810370456.5A CN108383802B (en) 2018-04-24 2018-04-24 Method for synthesizing 4-aryl-3-nitroisoxazole by catalyzing aryl aldehyde and nitromethane with copper salt

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810370456.5A CN108383802B (en) 2018-04-24 2018-04-24 Method for synthesizing 4-aryl-3-nitroisoxazole by catalyzing aryl aldehyde and nitromethane with copper salt

Publications (2)

Publication Number Publication Date
CN108383802A true CN108383802A (en) 2018-08-10
CN108383802B CN108383802B (en) 2020-01-07

Family

ID=63065830

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810370456.5A Active CN108383802B (en) 2018-04-24 2018-04-24 Method for synthesizing 4-aryl-3-nitroisoxazole by catalyzing aryl aldehyde and nitromethane with copper salt

Country Status (1)

Country Link
CN (1) CN108383802B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110963977A (en) * 2019-12-11 2020-04-07 常州大学 Synthesis method of oxazole heterocyclic compound

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110963977A (en) * 2019-12-11 2020-04-07 常州大学 Synthesis method of oxazole heterocyclic compound

Also Published As

Publication number Publication date
CN108383802B (en) 2020-01-07

Similar Documents

Publication Publication Date Title
Zhang et al. Silver-catalyzed formal [3+ 2]-cycloaddition of α-trifluoromethylated methyl isocyanides: a facile stereoselective synthesis of CF 3-substituted heterocycles
Harichandran et al. Boric acid catalyzed efficient synthesis of symmetrical N, N′-alkylidene bisamides
CN110240568B (en) Trisubstituted pyridazine derivative and preparation method thereof
CN109867643B (en) Polysubstituted furan derivative and synthesis thereof
CN108912044B (en) Method for synthesizing polysubstituted pyridine by using copper-catalyzed alkenyl azide
CN108658883B (en) Method for synthesizing isoxazole derivative by catalyzing aryl aldehyde and nitromethane with copper salt
CN108383802A (en) A kind of mantoquita catalysis aryl aldehyde and nitromethane heterocyclic compound at 4- aryl -3- nitro isoxazoles method
Li et al. First synthesis of unexpected functionalized trifluoromethylated 8-oxa-2, 4-diazaspiro [5.5] undecanes via one-pot MCRs
CN110105285B (en) Trisubstituted pyrazole derivative and preparation method thereof
CN110204533B (en) Preparation method of 4- (isochromen-1-yl) isoquinoline derivative
Xiao et al. CuI-catalyzed cross-coupling of terminal alkynes with dialkoxycarbenes: a general method for the synthesis of unsymmetrical propargylic acetals
Chen et al. TfOH-promoted synthesis of 4, 5-dihydrooxazolo [5, 4-c] isoquinolines via formal [3+ 2] cycloaddition of 4-diazoisoquinolin-3-one and benzonitriles
Ali et al. Reaction behaviour of arylamines with nitroalkenes in the presence of bismuth (iii) triflate: an easy access to 2, 3-dialkylquinolines
CN108658884B (en) Synthetic method of 3-nitroisoxazole derivative
Sun et al. Synthesis of polyfunctionalized acrylates via one-pot reactions of arylamines, methyl propiolate, aromatic aldehydes, and active methylene compounds
Alam et al. The Advances and Applications of Arynes and Their Precursors to Synthesize the Heterocyclic Compounds: A Review
CN114380790B (en) Polysubstituted thiopyran derivative and synthetic method thereof
CN115477627A (en) Polysubstituted 2-furanone compound and synthesis method thereof
Yang et al. Regioselective Synthesis of 2, 6‐Dimethyl‐3, 5‐bis [(3‐aryl‐5‐trifluoromethyl)‐isoxazol‐4‐carbonyl]‐pyridine Derivatives
CN110117258B (en) Preparation method of 2,4, 6-triaryl substituted pyrimidine compound
CN107417623B (en) Method for synthesizing 5-diarylaminobenzimidazole derivative in one step
CN104327025A (en) Preparation method of 4-aryltetralin lactone derivatives
Wang et al. Sc (OTf) 3-mediated 1, 3-dipolar cycloaddition–ring cleavage–rearrangement: a highly stereoselective access to Z-β-enaminonitriles
Nadaf et al. Visible Light Assisted Hantzsch Reaction: Synthesis of Polycyclic Dihydropyridines
CN107459530A (en) A kind of 1,3 isoquinolin derovatives of novel silicon base substitution and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20240902

Address after: No. 87, Suzhong Avenue, Shangku Comprehensive Industrial Park, Korla City, Bazhou, Xinjiang Uygur Autonomous Region, 841000

Patentee after: Xinjiang Puhesu New Environmental Protection Materials Co.,Ltd.

Country or region after: China

Address before: No.1 shijihu Chuangye Road, Yuanjiang City, Yiyang City, Hunan Province 413100

Patentee before: YUANJIANG HUALONG CATALYST TECHNOLOGY Co.,Ltd.

Country or region before: China