Method for efficient catalysis of knoevenagel condensation reaction by porphyrin and quaternary ammonium salt synergistic catalytic system

Abstract

The method for high-efficiency catalysis of Knoevenagel condensation reaction by a porphyrin and quaternary ammonium salt synergistic catalytic system belongs to the technical field of catalyzing Knoevenagel condensation reaction. The synergistic catalytic system comprises a porphyrin ligand and a quaternary ammonium salt compound. The method for high-efficiency catalysis of Knoevenagel condensation reaction of aldehyde ketone and active methylene to generate methylene malononitrile compounds is to use the porphyrin ligand and the quaternary ammonium salt as a synergistic catalytic system to catalyze the condensation of aldehyde ketone and active methylene to generate methylene malononitrile compounds. The porphyrin ligand and quaternary ammonium salt synergistic catalytic system avoids the disadvantages of environmental pollution and difficult recycling of traditional basic homogeneous catalysts, so that the porphyrin ligand and quaternary ammonium salt synergistic catalytic system is easy to operate and recycle, has universal practicability, can be used by ordinary experimental operators, and provides an easy-to-operate, inexpensive and efficient route for the synthesis of methylene malononitrile compounds, which has a popular prospect.

Description

Technical Field

[0001] This invention belongs to the technical field of catalytic Knoevenagel condensation reaction methods, and relates to a method for efficiently catalyzing the Knoevenagel condensation reaction using a porphyrin and quaternary ammonium salt synergistic catalytic system. Background Technology

[0002] The Knoevenagel condensation reaction is one of the most well-known reactions in organic chemistry for forming C–C bonds. It typically involves activating the active methylene group under the action of a basic catalyst. The activated methylene group then undergoes a nucleophilic addition reaction with a carbonyl group, followed by dehydration to form a C–C bond. In 1894, Emil Knoevenagel first discovered the condensation reaction between aliphatic formaldehyde and diethyl malonate, considered a pioneer in the field of C–C bond construction, hence the name Knoevenagel condensation reaction. Products obtained from the Knoevenagel condensation reaction are widely used as intermediates in the synthesis of specialty and fine chemicals, such as carbocyclic compounds, substituted alkenes, bioactive compounds, therapeutic drugs, calcium antagonists, natural products, functional polymers, coumarin derivatives, flavorings, and fragrances. Traditionally, the Knoevenagel condensation reaction is catalyzed under homogeneous conditions using catalysts such as primary amines, secondary amines, tertiary amines, ammonium salts, ionic liquids, amino acids, Lewis acids such as ZnCl2, TiCl4, Al2O3, and LaCl3, and organometallic catalysts. However, homogeneous catalysis has several drawbacks, including difficulties in catalyst recovery, the need for high reaction temperatures, difficulties in product separation, and the use of large amounts of solvent, leading to environmental pollution. To achieve catalyst separation and recovery, avoid generating large amounts of pollutants, and retain similar active sites as homogeneous catalysts, the heterogeneity of homogeneous catalysts has become an important research area in academia.

[0003] To date, many heterogeneous catalysts have been used to catalyze the Knoevenagel reaction.

[0004] (1) In 2022, Zuo et al. synthesized three mixed porphyrin compounds, icpp (1-3), using 4-formylbenzoic acid and 4-imidazolium formaldehyde as raw materials. Then, using icpp (1-3), timp, and tcpp as raw materials, they reacted to obtain five amorphous or crystalline Zr-MOF-SPUZ (1-5). Under solvent-free conditions, using aldehydes and malononitrile as raw materials, they studied the catalytic activity of the synthesized porphyrins and MOFs for the Knoevenagel condensation reaction. Among them, the amorphous MOF SPUZ-1 exhibited the highest catalytic activity. Furthermore, further studies on different substituted aliphatic and aromatic aldehydes showed that most substrates were converted within a low catalyst loading (1 mol%) and a short reaction time (5-30 min). In addition, SPUZ-1, as a heterogeneous catalyst, could be recycled seven times without significant activity loss.

[0005]

[0006] (2) In 2020, Sahu et al. prepared a nitrogen-rich imine-functionalized nanoporous organic framework polymer, TpTabPOP, using DMF as a solvent at room temperature and a simple solution-phase polymerization method with 1,3,5-tricarboxymethyl phloroglucinol (Tp) and 1,2,4-triaminobenzene (Tab) as raw materials. This polymer exhibited good catalytic performance for the Knoevenagel condensation reaction of aromatic aldehydes and malononitriles at room temperature, with GC yields of 86.7-98.7%. After repeated use, the recovered porous TpTabPOP maintained its stability and catalytic activity.

[0007]

[0008] (3) In 2019, Clacens et al. functionalized three commercial carbonaceous materials, including Darco KB-G, Norit SX 2, and Vulcan XC 72, with phenyl primary amines via diazo coupling. The three carbon-based basic solids were characterized by spectrometry, and their catalytic efficiency for the Knoevenagel condensation of furfural and malononitrile was investigated. At atmospheric pressure and 40 °C, Darco-0.5PDA was the most efficient catalyst for Knoevenagel condensation among the three carbon-based solids. However, Darco-0.5PDA deactivated after several cycles, which may be due to hydrogen bonds between the amino group of the catalyst and the carbonyl group of furfural and the Knoevenagel product.

[0009]

[0010] The synthesis of (2-furanylmethylene)malononitrile(FMMN)catalyzed by an amino-functionalized carbonaceous catalyst.

[0011]

[0012] The synthesis of (2-furanylmethylene)malononitrile(FMMN)catalyzed byDarco-0.5IM catalyst.

[0013] (4) In 2011, Verdía and colleagues developed a green approach to recover the ionic liquid 1,3-dimethylimidazolium methyl sulfate [MMIm][MSO4] as both solvent and catalyst, and para-substituted benzaldehyde and malononitrile as model substrates, achieving the recovery of 1,3-dimethylimidazolium methyl sulfate [MMIm][MSO4] in a Knoevenagel condensation reaction at room temperature. However, when using a dried ionic liquid as a catalyst, the yield decreased significantly even with extended reaction times, with optimal results obtained when the water content in the ionic liquid was 2%. The study found that water in the ionic liquid provides a lubricating effect, thereby reducing the electrostatic interaction between the cations and anions of the ionic liquid and promoting substrate activation. Furthermore, recovery experiments showed that the yield did not decrease significantly after six recovery experiments, but the reaction time increased from 2 minutes in the first recovery experiment to 240 minutes in the sixth recovery experiment.

[0014]

[0015] While the aforementioned heterogeneous catalysts exhibit good catalytic performance in the condensation of aldehydes and ketones with active methylene groups to form methylene malononitriles, these catalysts require harsh reaction conditions and long reaction times. The complex synthesis and characterization processes increase the cost of catalyst synthesis and limit their general applicability, making them unsuitable for ordinary laboratory use. Therefore, developing a simple and efficient catalytic system is essential. Summary of the Invention

[0016] To overcome the environmental pollution and difficulty in recycling of traditional basic homogeneous catalysts, and the relatively harsh reaction conditions, long reaction times, and complex preparation and characterization of heterogeneous catalysts, this invention provides a method for catalyzing the condensation of aldehydes and ketones with active methylene groups to generate methylene malononitriles using a porphyrin-quaternary ammonium salt synergistic catalytic system. This catalytic system is environmentally friendly and relatively simple to prepare. Furthermore, this method offers advantages such as high catalytic efficiency, mild reaction conditions, simple post-reaction processing, and the recyclability of the catalytic system, making it promising for industrial applications.

[0017] This invention is achieved through the following technical solution

[0018] This invention provides a catalytic system in which porphyrin and quaternary ammonium salt synergize, comprising quaternary ammonium salt, porphyrin and metalloporphyrin.

[0019] Furthermore, the porphyrin is one or more of the porphyrin ligands timp, icpp-1, icpp-2, icpp-3, tcpp, tcpp-COOMe, or metal porphyrins composed of cobalt, manganese, iron, or zirconium; the quaternary ammonium salt is selected from one or a mixture of choline, choline chloride, choline bromide, and choline iodide; the molar ratio is porphyrin:quaternary ammonium salt = (1-20):(20-300).

[0020] Furthermore, the reaction conditions are either solvent-free or solvent-containing; when the reaction conditions are solvent-containing, the solvent is one or more of water, methanol, ethanol, or isopropanol.

[0021] Furthermore, after the reaction is completed, the synergistic catalytic system is recovered and reused by extraction. The recovered catalytic system is a black solid and can be reused to catalyze the reaction. The extraction solvent is one or more of ethyl acetate, dichloromethane, chloroform or acetone.

[0022] This invention provides a method for catalyzing the condensation of aldehydes and ketones with active methylene groups to generate methylene malononitriles using a porphyrin-quaternary ammonium salt synergistic catalytic system, the general reaction formula of which is shown below;

[0023]

[0024] Includes the following steps:

[0025] Using aldehydes and ketones and active methylene groups as substrates, and a synergistic catalytic system composed of porphyrin and quaternary ammonium salt as catalyst, a reaction system is formed under solvent-free or solvent-containing conditions. The reaction is carried out at 30–60 °C for 1–10 min to obtain methylene malononitriles.

[0026] Furthermore, the reaction temperature is 25–80℃, and the reaction time is 1–10 min;

[0027] Furthermore, in the molar ratio, porphyrin: quaternary ammonium salt: aldehydes and ketones: active methylene group = (1-20): (20-300): (100-2000): (110-2200).

[0028] The aldehyde and ketone compounds are selected from one of monoaryl aldehydes, monoaryl heterol aldehydes, aliphatic aldehydes, diaryl ketones, diaryl heterol ketones, monoaryl-alkyl ketones, monoaryl heterol-alkyl ketones, and aliphatic ketone compounds; the active methylene group is selected from one of malononitrile, ethyl cyanoacetate, cyanoacetic acid, and N,N-diethylcyanoacetamide.

[0029] Furthermore, the structural formulas of the aforementioned monoaryl aldehydes and monoaryl heterol aldehydes are as follows:

[0030] Ar 1 -CHO

[0031] Among them, Ar 1 It is one of aryl, aromatic heterol, or fused ring;

[0032] Furthermore, the structural formulas of the aforementioned diaryl ketones and diaryl heterol ketones are as follows:

[0033]

[0034] Among them, Ar 2 Ar 3 Each is individually selected from aryl, aromatic heterol, and fused ring;

[0035] Furthermore, the structural formulas of the aforementioned monoaryl-alkyl ketones and monoarylhexyl-alkyl ketones are as follows:

[0036]

[0037] Among them, Ar 4 Each is individually selected from aryl, aryl heterol, and fused ring; R 1 It is a C1-C8 alkyl, C1-C8 cycloalkyl, or C1-C8 alkoxy;

[0038] In the above structural formula, when Ar 1 Ar 2 Ar 3 Ar 4 When it is aryl, the aryl group is selected from substituted or unsubstituted five- or six-membered aromatic rings and the substituents are one or more; the substituents of the aryl group are selected from H, C1-C8 alkyl, C1-C8 alkoxy, halogroup, OH, CF3, NO2, CN and CHO.

[0039] When Ar 1 Ar 2Ar 3 Ar 4 When it is an aromatic heterocycle, the aromatic heterocycle is a substituted or unsubstituted five- or six-membered aromatic heterocycle, and the heteroatom on the aromatic heterocycle is one or more of N, S, and O; the substituent of the aromatic heterocycle is one or more of CH3, Et, tBu, OCH3, F, Cl, Br, CF3, NO2, CN, and CHO.

[0040] Furthermore, the structural formula of the aliphatic aldehydes is as follows:

[0041] R 2 ·CHO

[0042] Among them, R 2 It represents one of H, C1-C8 alkyl, C1-C8 cycloalkyl, C1-C8 alkoxy, halogroup, OH, CF3, NO2, CN, and CHO;

[0043] Furthermore, the structural formula of the aliphatic ketone compound is as follows:

[0044]

[0045] Where R 3 R 4 It can be used alone to represent C1-C8 alkyl or C1-C8 cycloalkyl.

[0046] In the above structural formula, when Ar 1 Ar 2 Ar 3 Ar 4 When it is aryl, the aryl group is selected from substituted or unsubstituted five- or six-membered aromatic rings and the substituents are one or more; the substituents of the aryl group are selected from H, C1-C8 alkyl, C1-C8 alkoxy, halogroup, OH, CF3, NO2, CN and CHO.

[0047] When Ar 1 Ar 2 Ar 3 Ar 4 When it is an aromatic heterocycle, the aromatic heterocycle is a substituted or unsubstituted five- or six-membered aromatic heterocycle, and the heteroatom on the aromatic heterocycle is one or more of N, S, and O; the substituent of the aromatic heterocycle is one or more of CH3, Et, tBu, OCH3, F, Cl, Br, CF3, NO2, CN, and CHO.

[0048] Furthermore, the structural formula of the aliphatic aldehydes is as follows:

[0049] R 2 ·CHO

[0050] Among them, R 2It represents one of H, C1-C8 alkyl, C1-C8 cycloalkyl, C1-C8 alkoxy, halogroup, OH, CF3, NO2, CN, and CHO;

[0051] Furthermore, the structural formula of the aliphatic ketone compound is as follows:

[0052]

[0053] Where R 3 R 4 It can be used alone to represent C1-C8 alkyl or C1-C8 cycloalkyl.

[0054] Furthermore, the active methylene group has the following structural formula:

[0055]

[0056] EWG1 is one of cyano or ethyl cyanoacetate; EWG1 is one of cyano, ethyl cyanoacetate, cyanoacetic acid, or N,N-diethylcyanoacetamide.

[0057] This route provides a simple, inexpensive, and efficient approach for the Knoevenagel condensation reaction.

[0058] Compared with the prior art, the present invention has the following advantages:

[0059] (1) This invention demonstrates through experiments that the method of catalyzing the condensation of aldehydes and ketones with active methylene groups to form methylene malononitriles using a synergistic catalytic system of porphyrin and quaternary ammonium salt has high catalytic activity and a separation yield of up to 95%. Moreover, the recovered synergistic catalytic system can be recycled.

[0060] (2) This invention utilizes quaternary ammonium salts and porphyrins in synergistic applications in the Knoevenagel condensation reaction. This catalytic system avoids the environmental pollution and difficulty in recycling associated with traditional alkaline catalysts, and eliminates the need for the synthesis, purification, and characterization of heterogeneous catalysts. This makes the catalytic system simple to operate, universally applicable, and usable by ordinary laboratory personnel. It provides a simple, inexpensive, and efficient route for the Knoevenagel condensation reaction.

[0061] (3) This invention provides a method for synthesizing methylene malononitrile compounds using a synergistic catalytic system of porphyrin and quaternary ammonium salt. This synergistic catalytic system has a very good catalytic effect on the condensation of aldehydes and ketones with active methylene groups, with a short reaction time and a yield of up to 99%. It has the advantages of being simple, inexpensive and efficient.

[0062] (4) The present invention provides a method for preparing methylene malononitrile compounds by catalyzing the condensation of aldehydes and ketones with active methylene groups using a porphyrin and quaternary ammonium salt synergistic catalytic system. The substrate conversion rate of this method is ≥92%. Attached Figure Description

[0063] Figure 1 The phenylmethylene malononitrile prepared in Example 1 of this invention 1 H-NMR spectrum.

[0064] Figure 2 The 2-fluorophenylmethylene malononitrile prepared in Example 6 of this invention 1 H-NMR spectrum.

[0065] Figure 3 3-Fluorophenylmethylene malononitrile prepared in Example 7 of this invention 1 H-NMR spectrum.

[0066] Figure 4 The 4-fluorophenylmethylene malononitrile prepared in Example 8 of this invention 1 H-NMR spectrum.

[0067] Figure 5 2-Chlorophenylmethylene malononitrile prepared in Example 9 of this invention 1 H-NMR spectrum.

[0068] Figure 6 2-Methoxyphenylmethylene malononitrile prepared in Example 10 of this invention 1 H-NMR spectrum.

[0069] Figure 7 2-Nitrophenylmethylene malononitrile prepared in Example 11 of this invention 1 H-NMR spectrum.

[0070] Figure 8 2-Naphthylmethylene malononitrile prepared in Example 12 of this invention 1 H-NMR spectrum.

[0071] Figure 9 (2-furanmethylene)malononitrile prepared in Example 13 of this invention 1 H-NMR spectrum.

[0072] Figure 10 2-(thiophene-2-ylmethylene)malononitrile prepared in Example 14 of this invention 1 H-NMR spectrum.

[0073] Figure 11 2-Cyclohexylmalononitrile prepared in Example 15 of this invention 1 H-NMR spectrum.

[0074] Figure 12 The entacapone acid prepared in Example 16 of this invention 1 H-NMR spectrum.

[0075] Figure 13 Entacapone prepared in Example 17 of this invention 1 H-NMR spectrum. Detailed Implementation

[0076] The following embodiments will help to understand the purpose, features, advantages, and technical methods of the present invention, but should not be construed as limiting the scope of the invention. The implementation conditions used in the embodiments can be further adjusted according to different requirements of specific applications, and the implementation conditions not specified are those in conventional experiments.

[0077] In the following embodiments, 1 The test solvent used for H-NMR is CDCl3 or DMSO-d6.

[0078] In the following examples, the recovered catalyst was detected using an infrared spectrometer (FI-IR).

[0079] Table 1. Investigation of catalyst dosage and solvent usage

[0080]

[0081] Reaction conditions: benzaldehyde (1 mmol), malononitrile (1.1 mmol), solvent (0.6 mL), reaction at 30 °C. a The yield was determined by liquid chromatography.

[0082] Example 1: Preparation of phenylmethylene malononitrile (solvent-free conditions)

[0083] Take a dry 5 mL round-bottom flask equipped with a magnetic stirrer, add malononitrile (1.1 equiv), timp (1 mol%), and ChCl (4 mol%) to the flask, and stir slowly in an oil bath at 30 °C until the malononitrile and catalyst are evenly mixed. Then add benzaldehyde (1 mmol) to the reaction flask, maintain the temperature, and stir moderately until the reaction is complete. Stop the reaction. Add an appropriate amount of organic solvent to the reaction system to dissolve the product. At this time, the catalytic system layer and the organic phase separate. Separate the organic phase and the catalytic system layer, and wash the catalytic system layer three times with organic solvent (5 mL * 3). Combine the organic phases, wash with saturated brine, dry with anhydrous Na2SO4, filter, remove the solvent under reduced pressure, and recrystallize with ethanol to obtain white crystals 3a. 1¹H NMR (600 MHz, DMSO-d⁶) δ 8.55 (s, 1H), 8.01–7.92 (m, 2H), 7.75–7.57 (m, 3H), its ¹H NMR spectrum is shown in [reference needed]. Figure 1 ,

[0084] Its corresponding structure is:

[0085]

[0086] Under stirring, the reaction system gradually solidified, and TLC monitoring confirmed the completeness of the reaction. An organic solvent was added to the reaction system to dissolve the product. At this point, the synergistic catalytic system and the organic phase separated into layers. The organic phase and the synergistic catalytic system layer were separated by extraction. The synergistic catalytic system layer, after removing residual solvent, yielded a black solid, which was the recovered synergistic catalytic system. Analysis of this synergistic catalytic system revealed that ChCl and timp did not form a new catalyst during the reaction. Further analysis of the catalytic system showed that the characteristic elements contained in ChCl and timp were uniformly distributed. These results indicate that this catalytic system is a heterogeneous catalytic system with synergistic effects of ChCl and timp.

[0087] Example 2: Preparation of phenylmethylene malononitrile (H2O as solvent)

[0088] Take a dry 5 mL round-bottom flask equipped with a magnetic stirrer, and add benzaldehyde (1 mmol), malononitrile (1.1 equiv), timp (1 mol%), ChCl (4 mol%), and 1.5 mL H₂O to the flask. Stir the reaction at room temperature until the reaction system solidifies. Then, add an organic solvent to the reaction system to dissolve the product. At this time, the catalytic system layer and the organic phase separate. Separate the organic phase and the catalytic system layer, and wash the catalytic system layer three times with organic solvent (5 mL * 3). Combine the organic phases, wash with saturated brine, dry with anhydrous Na₂SO₄, filter, remove the solvent under reduced pressure, and recrystallize with ethanol to obtain white crystals 3a. 1 ¹H NMR (600 MHz, DMSO-d⁶) δ 8.55 (s, 1H), 8.01–7.92 (m, 2H), 7.75–7.57 (m, 3H), its ¹H NMR spectrum is shown in [reference needed]. Figure 1 ;

[0089] Its corresponding structure is:

[0090]

[0091] Example 3: Preparation of phenylmethylene malononitrile (MeOH as solvent)

[0092] Take a dry 5 mL round-bottom flask equipped with a magnetic stirrer, and add benzaldehyde (1 mmol), malononitrile (1.1 equiv), timp (1 mol%), ChCl (4 mol%), and 1.5 mL MeOH to the flask. Stir the reaction at room temperature until the reaction system solidifies. Then, add an organic solvent to the reaction system to dissolve the product. At this time, the catalytic system layer and the organic phase separate. Separate the organic phase and the catalytic system layer, and wash the catalytic system layer three times with organic solvent (5 mL * 3). Combine the organic phases, wash with saturated brine, dry with anhydrous Na2SO4, filter, remove the solvent under reduced pressure, and recrystallize with ethanol to obtain white crystals 3a. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.55 (s, 1H), 8.01–7.92 (m, 2H), 7.75–7.57 (m, 3H), its ¹H NMR spectrum is shown in [reference needed]. Figure 1 ;

[0093] Its corresponding structure is:

[0094]

[0095] Example 4: Preparation of phenylmethylene malononitrile (EtOH as solvent)

[0096] Take a dry 5 mL round-bottom flask equipped with a magnetic stirrer, and add benzaldehyde (1 mmol), malononitrile (1.1 equiv), timp (1 mol%), ChCl (4 mol%), and 1.5 mL EtOH to the flask. Stir the reaction at room temperature until the reaction system solidifies. Then, add an organic solvent to the reaction system to dissolve the product. At this time, the catalytic system layer and the organic phase separate. Separate the organic phase and the catalytic system layer, and wash the catalytic system layer three times with organic solvent (5 mL * 3). Combine the organic phases, wash with saturated brine, dry with anhydrous Na2SO4, filter, remove the solvent under reduced pressure, and recrystallize with ethanol to obtain white crystals 3a. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.55 (s, 1H), 8.01–7.92 (m, 2H), 7.75–7.57 (m, 3H), its ¹H NMR spectrum is shown in [reference needed]. Figure 1 ;

[0097] Its corresponding structure is:

[0098]

[0099] Example 5: Preparation of phenylmethylene malononitrile ( i PrOH as a solvent)

[0100] Take a dry 5 mL round-bottom flask equipped with a magnetic stirrer, and add benzaldehyde (1 mmol), malononitrile (1.1 equiv), timp (1 mol%), ChCl (4 mol%), and 1.5 mL of... i PrOH was added to a round-bottom flask and stirred at room temperature until the reaction system solidified. Then, an organic solvent was added to the reaction system to dissolve the product. At this point, the catalytic system layer and the organic phase separated. The organic phase and the catalytic system layer were separated, and the catalytic system layer was washed three times with organic solvent (5 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. The product was then recrystallized with ethanol to obtain white crystals 3a. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.55 (s, 1H), 8.01–7.92 (m, 2H), 7.75–7.57 (m, 3H), its ¹H NMR spectrum is shown in [reference needed]. Figure 1 ;

[0101] Its corresponding structure is:

[0102]

[0103] Example 6: Preparation of 2-fluorophenylmethylene malononitrile

[0104] The procedure is as described in Example 1, with the differences shown in Table 1, and a white solid is obtained. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.60 (s, 1H), 8.07 (td, J = 7.7, 1.7Hz, 1H), 7.76 (dddd, J = 8.7, 7.3, 5.5, 1.7Hz, 1H), 7.50–7.43 (m, 2H). Its ¹H NMR spectrum is shown below. Figure 2 ;

[0105] Its corresponding structure is:

[0106]

[0107] Example 7: Preparation of 3-fluorophenylmethylene malononitrile

[0108] The procedure is as described in Example 1, with the differences shown in Table 1, and a white solid is obtained. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.57 (s, ¹H), 7.83–7.77 (m, ¹H), 7.74 (dt, J = 9.9, 2.1 Hz, ¹H), 7.70 (td, J = 8.1, 5.9 Hz, ¹H), 7.58 (tdd, J = 8.5, 2.6, 0.9 Hz, ¹H), its ¹H NMR spectrum is shown in [reference needed]. Figure 3 ;

[0109] Its corresponding structure is:

[0110]

[0111] Example 8: Preparation of 4-fluorophenylmethylene malononitrile

[0112] The procedure is as described in Example 1, with the differences shown in Table 1, and a white solid is obtained. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.55 (s, ¹H), 8.08–8.02 (m, ²H), 7.54–7.47 (m, ²H), its ¹H NMR spectrum is shown in [reference needed]. Figure 4 ;

[0113] Its corresponding structure is:

[0114]

[0115] Example 9: Preparation of 2-chlorophenylmethylene malononitrile

[0116] The procedure is as described in Example 1, with the differences shown in Table 1, and a yellow solid is obtained. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.68 (s, 1H), 8.03 (dd, J=7.8, 1.5Hz, 1H), 7.75–7.65 (m, 2H), 7.62–7.56 (m, 1H), its ¹H NMR spectrum is shown in [reference needed]. Figure 5 ;

[0117] Its corresponding structure is:

[0118]

[0119] Example 10: Preparation of 2-methoxyphenylmethylene malononitrile

[0120] The procedure is as described in Example 1, with the differences shown in Table 1, and a yellow solid is obtained. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.48 (s, 1H), 7.97 (dd, J = 7.9, 1.6Hz, 1H), 7.68 (ddd, J = 8.7, 7.3, 1.7Hz, 1H), 7.24 (dd, J = 8.5, 1.0Hz, 1H), 7.18–7.12 (m, 1H), 3.91 (s, 3H). Its ¹H NMR spectrum is shown in [reference needed]. Figure 6 ;

[0121] Its corresponding structure is:

[0122]

[0123] Example 112: Preparation of 1,2-Nitrophenylmethylene malononitrile

[0124] The procedure is as described in Example 1, with the differences shown in Table 1, and a yellow solid is obtained. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.98 (s, ¹H), 8.35 (dd, J = 8.2, 1.2 Hz, ¹H), 8.02 (td, J = 7.5, 1.2 Hz, ¹H), 7.96 (dt, J = 7.6, 1.1 Hz, ¹H), 7.94–7.87 (m, ¹H). Its ¹H NMR spectrum is shown in [reference needed]. Figure 7 ;

[0125] Its corresponding structure is:

[0126]

[0127] Example 122: Preparation of 2-Naphthylmethylenemalononitrile

[0128] The procedure is as described in Example 1, with the differences shown in Table 1, and a yellow solid is obtained. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.68 (s, 1H), 8.51–8.47 (m, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.11–8.06 (m, 2H), 8.04 (dd, J = 8.2, 1.1 Hz, 1H), 7.75 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.68 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H). Its ¹H NMR spectrum is shown in [reference needed]. Figure 8 ;

[0129] Its corresponding structure is:

[0130]

[0131] Example 13: Preparation of (2-furanmethylene)malononitrile

[0132] The procedure is as described in Example 1, with the differences shown in Table 1, and a brown solid is obtained. 1 ¹H NMR (400MHz, Chloroform-d) δ 7.80 (d, J = 1.7 Hz, 1H), 7.51 (s, 1H), 7.37 (d, J = 3.7 Hz, 1H), 6.72 (dd, J = 3.8, 1.7 Hz, 1H), its ¹H NMR spectrum is shown in [reference needed]. Figure 9 ;

[0133] Its corresponding structure is:

[0134]

[0135] Example 14: Preparation of 2-(thiophene-2-ylmethylene)malononitrile

[0136] The procedure was as described in Example 1, with differences shown in Table 1, yielding a brown solid. ¹H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J = 6.1 Hz, 2H), 7.81 (d, J = 3.3 Hz, 1H), 7.30–7.26 (m, 1H). Its ¹H NMR spectrum is shown below. Figure 10 ;

[0137] Its corresponding structure is:

[0138]

[0139] Example 15: Preparation of 2-cyclohexylmalononitrile

[0140] The procedure was as described in Example 1, with differences shown in Table 1, yielding a colorless liquid. ¹H NMR: (400MHz, CDCl₃) δ 2.66 (t, J = 6.3Hz, 4H), 1.80 (m, 4H), 1.68 (m, 2H) ppm. Its ¹H NMR spectrum is shown below. Figure 11 ;

[0141] Its corresponding structure is:

[0142]

[0143] Example 16: Preparation of entacapone

[0144] The procedure is as described in Example 1, with the differences shown in Table 1, and a yellow solid is obtained. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.22 (s, ¹H), 8.07 (d, J = 2.2Hz, ¹H), 7.87 (d, J = 2.2Hz, ¹H). Its ¹H NMR spectrum is shown below. Figure 12 ;

[0145] Its corresponding structure is:

[0146]

[0147] Example 17: Preparation of entacapone

[0148] The procedure is as described in Example 1, with the differences shown in Table 1, and a yellow solid is obtained. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 10.93 (s, 2H), 7.93 (d, J = 2.2Hz, 1H), 7.75 (d, J = 2.2Hz, 1H), 7.64 (s, 1H), 3.41 (s, 4H), 1.15 (s, 6H). Its ¹H NMR spectrum is shown below. Figure 13 ;

[0149] Its corresponding structure is:

[0150]

[0151] Comparative Example 1

[0152] A method for catalytic condensation of aldehydes and ketones with active methylene groups to generate methylene malononitriles is described in the general procedure of Example 1, with the differences shown in Table 1. The amount of quaternary ammonium salt used is 1 mol%. As can be seen from Table 1, when the amount of quaternary ammonium salt is reduced, the reaction time is extended to 7 min and the yield is reduced to 97%.

[0153] Comparative Example 2

[0154] A method for catalytic condensation of aldehydes and ketones with active methylene groups to generate methylene malononitriles is described. The operation is as shown in the general method of Example 1, with the difference shown in Table 1. The amount of quaternary ammonium salt used is 8 mol%. As can be seen from Table 1, with the increase in the amount of quaternary ammonium salt, the reaction time is 4 min, and the yield is 99%. Compared with Example 1, the reaction time is not significantly shortened and the yield is not significantly improved.

[0155] Comparative Example 3

[0156] A method for catalytic condensation of aldehydes and ketones with active methylene groups to generate methylene malononitriles is described. The operation is as shown in the general method of Example 1, with the difference shown in Table 1. The amount of quaternary ammonium salt used is 10 mol%. As can be seen from Table 1, with the increase in the amount of quaternary ammonium salt, the reaction time is 4 min, and the yield is 99%. Compared with Example 1, the reaction time is not significantly shortened and the yield is not significantly improved.

[0157] Comparative Example 4

[0158] A method for catalytic condensation of aldehydes and ketones with active methylene groups to generate methylene malononitriles is described. The operation is as shown in the general method of Example 1, with the difference shown in Table 1. The amount of quaternary ammonium salt used is 14 mol%. As can be seen from Table 1, with the increase in the amount of quaternary ammonium salt, the reaction time is 4 min, and the yield is 99%. Compared with Example 1, the reaction time is not significantly shortened and the yield is not significantly improved.

[0159] Comparative Example 5

[0160] A method for catalytic condensation of aldehydes and ketones with active methylene groups to generate methylene malononitriles is described. The operation is as shown in Example 1, with the difference shown in Table 1. The amount of porphyrin used is 2 mol%. As can be seen from Table 1, with the increase of porphyrin amount, the reaction time is 4 min and the yield is 99%. Compared with Example 1, the reaction time is not significantly shortened and the yield is not significantly improved.

[0161] Comparative Example 6

[0162] A method for catalytic condensation of aldehydes and ketones with active methylene groups to generate methylene malononitriles is provided. The operation is as shown in the general method of Example 1, with the difference shown in Table 1. Porphyrin is not added. As can be seen from Table 1, the reaction time is greater than 60 min without porphyrin, which is significantly longer than that in Example 1.

[0163] Comparative Example 7

[0164] A method for catalytic condensation of aldehydes and ketones with active methylene groups to generate methylene malononitriles is provided. The operation is as shown in the general method of Example 1, with the difference shown in Table 1. Quaternary ammonium salts are not added. As can be seen from Table 1, the reaction time is greater than 60 min without the addition of quaternary ammonium salts, which is significantly longer than that of Example 1.

[0165] Comparative Example 8

[0166] A method for catalytic condensation of aldehydes and ketones with active methylene groups to generate methylene malononitriles is disclosed. The operation is as shown in the general method of Example 1, with the difference shown in Table 1. No co-catalytic system is added. As can be seen from Table 1, the reaction time is greater than 60 min without the co-catalytic system, which is significantly longer than that of Example 1.

Claims

1. A synergistic catalytic system of porphyrin and quaternary ammonium salt, characterized in that, It is composed of porphyrin or metalporphyrin and quaternary ammonium salt; wherein the porphyrin or metalporphyrin is one or more of the porphyrin ligands timp, icpp-1, icpp-2, icpp-3, tcpp, tcpp-COOMe or metalporphyrins composed of cobalt, manganese, iron or zirconium. The quaternary ammonium salt is selected from one or a mixture of several of choline, choline chloride, choline bromide and choline iodide.

2. The porphyrin-quaternary ammonium salt synergistic catalytic system according to claim 1, characterized in that, The composition of the porphyrin or metalporphyrin and quaternary ammonium salt is as follows, in molar ratio: porphyrin or metalporphyrin: quaternary ammonium salt = (1-20):(20-300).

3. The application of the porphyrin and quaternary ammonium salt synergistic catalytic system according to claim 1 in the catalytic Knoevenagel condensation reaction, characterized in that, The Knoevenagel condensation reaction is a reaction in which aldehydes and ketones condense with an active methylene group to form methylene malononitriles; wherein the aldehydes and ketones are selected from one of monoaryl aldehydes, monoaryl heterol aldehydes, aliphatic aldehydes, diaryl ketones, diaryl heterol ketones, monoaryl-alkyl ketones, monoaryl heterol-alkyl ketones, and aliphatic ketones.

4. The application of the porphyrin and quaternary ammonium salt synergistic catalytic system according to claim 3 in the catalytic Knoevenagel condensation reaction, characterized in that, The reaction includes the following steps: using aldehydes and ketones and active methylene groups as substrates, and a synergistic catalytic system composed of porphyrins and quaternary ammonium salts as catalysts, the reaction is carried out under solvent-free or solvent-containing conditions, and after the reaction is completed, methylene malononitrile compounds are obtained.

5. The application of the porphyrin and quaternary ammonium salt synergistic catalytic system according to claim 4 in the catalytic Knoevenagel condensation reaction, characterized in that, The reaction temperature is 25~80℃, and the reaction time is 1~10 min; the molar ratio is porphyrin: quaternary ammonium salt: aldehyde ketone compound: active methylene = (1-20):(20-300):(100-2000):(110-2200).

6. The application of the porphyrin-quaternary ammonium salt synergistic catalytic system according to any one of claims 4-5 in the catalytic Knoevenagel condensation reaction, characterized in that, The active methylene group is selected from one of malononitrile, ethyl cyanoacetate, cyanoacetic acid, and N,N-diethylcyanoacetamide.

7. The application of the porphyrin and quaternary ammonium salt synergistic catalytic system according to claim 6 in the catalytic Knoevenagel condensation reaction, characterized in that, The structural formulas of the monoaryl aldehydes and monoaryl heterol aldehydes are as follows: ； Among them, Ar 1 It is one of aryl, aromatic heterol, or fused ring; The structural formulas of the aforementioned diaryl ketones and diaryl heterol ketones are as follows: ； Among them, Ar 2 Ar 3 Each is individually selected from aryl, aromatic heterol, and fused ring; The structural formulas of the monoaryl-alkyl ketones and monoarylhexyl-alkyl ketones are as follows: ； Among them, Ar 4 Each is individually selected from aryl, aryl heterol, and fused ring; R 1 It is a C1~C8 alkyl, C1~C8 cycloalkyl or C1~C8 alkoxy; The structural formulas of the aliphatic aldehydes are as follows: ； Among them, R 2 It represents one of H, C1~C8 alkyl, C1~C8 cycloalkyl, C1~C8 alkoxy, halogroup, OH, CF3, NO2, CN, and CHO; The structural formula of the aliphatic ketone compound is as follows: ； Where R 3 R 4 Individually represented as C1~C8 alkyl or C1~C8 cycloalkyl; The active methylene group has the following structural formula: ； EWG1 is one of cyano and ethyl cyanoacetate; EWG1 is one of cyano, ethyl cyanoacetate, cyanoacetic acid and N,N-diethylcyanoacetamide.

8. The application of the porphyrin and quaternary ammonium salt synergistic catalytic system according to claim 7 in the catalytic Knoevenagel condensation reaction, characterized in that, The Ar 1 Ar 2 Ar 3 Ar 4 When the aryl group is aryl, the aryl group is selected from substituted or unsubstituted five- or six-membered aromatic rings, and the substituents are one or more; the substituents of the aryl group are selected from H, C1-C8 alkyl, C1-C8 alkoxy, halogroup, OH, CF3, NO2, CN, and CHO; the Ar 1 Ar 2 Ar 3 Ar 4 When it is an aromatic heterocycle, the aromatic heterocycle is a substituted or unsubstituted five- or six-membered aromatic heterocycle, and the heteroatom on the aromatic heterocycle is one or more of N, S, and O; the substituent of the aromatic heterocycle is one or more of CH3, Et, tBu, OCH3, F, Cl, Br, CF3, NO2, CN, and CHO.

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