A zinc catalyst for selective reduction of unsaturated amides and its use

Abstract

This invention discloses a zinc catalyst and its application in the selective reduction of unsaturated amides to prepare unsaturated amines. The zinc catalyst is prepared by reacting zinc carboxylate salts and amine ligands as raw materials. After mixing with unsaturated amide compounds and a reducing agent in a solvent, the corresponding unsaturated amines can be obtained through reaction and post-treatment. This catalyst is green and inexpensive, stable in air without requiring an inert atmosphere, and exhibits mild reaction conditions, high product yield, and a wide range of applicable substrates. It is also suitable for highly challenging primary amide compounds, solving the problems of harsh reaction conditions, the need for inert atmosphere protection, and the high cost and instability of precious metal catalysts used in current hydrosilylation methods for reducing amide compounds. Therefore, it has broad application prospects.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis catalysis, specifically relating to a green zinc catalyst and a method for selectively reducing unsaturated amide compounds to unsaturated amines using the zinc catalyst. Background Technology

[0002] Amines are an important class of compounds with wide applications in the agrochemical and pharmaceutical industries, serving as additives, solvents, detergents, dyes, corrosion inhibitors, and fungicides. Reducing amides to amines is a simple method for synthesizing amines. However, the partial double bond feature of the CN group within the amide results in a planar configuration, which reduces the electrophilicity of the carbonyl carbon, making it less susceptible to nucleophilic attack. Therefore, selectively reducing the amide group in the presence of other unsaturated groups is challenging.

[0003] In recent decades, the selective hydrosilylation of amides has attracted increasing attention. In terms of reductive activity, primary amides < secondary amides < tertiary amides. While numerous reports have documented the hydrosilylation of more reactive tertiary or secondary amides, reports on the more challenging hydrosilylation of primary amides are very limited, with alkali metal-catalyzed hydrosilylation of primary amides only appearing in 2012. In 2012, a report (Angew. Chem. Int. Ed., 2012, 51 (7): 1662-1666.) described a complex process using two different iron catalysts in two consecutive reaction steps: one catalyst converts the primary amide to a nitrile, while the other reduces the nitrile to an amine. In 2019, Mandal et al. (Chem. Commun., 2019, 55 (79): 11868-11871.) first proposed that the [Mn(L)Cl] catalyst in the presence of KOtBu and PhSiH3 can reduce primary amides to primary amines via hydrosilylation, exhibiting excellent catalytic activity. Furthermore, by changing the reaction conditions, the product can be controlled to remain at the nitrile stage, representing a significant breakthrough in using a single catalyst to selectively convert primary amides to nitrile or amine. However, this catalyst suffers from poor stability and requires an inert atmosphere for the reaction. Additionally, the above methods suffer from drawbacks such as long reaction times, catalyst instability, stringent reaction conditions, high cost, and complex experimental procedures.

[0004] The development of inexpensive metal catalysts has greatly broadened the application prospects of non-precious metal catalysts in the hydrosilylation of amides. However, there are few studies on the use of zinc catalysts for the reduction of amides to amines, especially the use of inexpensive, green zinc catalysts to reduce primary amides to amines. Therefore, developing an inexpensive and highly selective catalyst for the selective reduction of amides is of great significance for the preparation of unsaturated amines. Summary of the Invention

[0005] The purpose of this invention is to provide a zinc catalyst and a method for effectively catalyzing the selective reduction of unsaturated amides to unsaturated amines. This method has the advantages of catalyst stability, low cost, simple operation, high product yield, and wide substrate compatibility.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A zinc catalyst for the selective reduction of unsaturated amides has the following general structural formula:

[0008] , where n=1~8, X=0 or N.

[0009] Furthermore, the zinc catalyst is prepared by stirring zinc carboxylate, amine ligand and solvent isopropyl ether at room temperature for 4 h, and then removing the solvent under vacuum; wherein the molar ratio of zinc carboxylate to amine ligand is 1:1.

[0010] Furthermore, the zinc carboxylate is a straight-chain or branched metallic zinc salt containing C2 to C9 carbon atoms.

[0011] Furthermore, the amine ligand is tetramethylethylenediamine or N,N-dimethylethanolamine.

[0012] Furthermore, the zinc catalyst is preferably any one of the following formulas (a)-(c):

[0013] .

[0014] The aforementioned zinc catalyst can be used to catalyze the selective reduction of unsaturated amides to prepare unsaturated amines. The application method involves mixing and reacting an unsaturated amide compound (II), a reducing agent, and a zinc catalyst (I) in a reaction solvent under a nitrogen or air atmosphere. The reaction solution is then post-treated to obtain the corresponding unsaturated amine (III). The chemical reaction formula is as follows:

[0015] , where R 1 It is an aromatic group, an unsaturated heterocyclic group, or an alkyl group; R 2 and R 3 It is an alkyl group or hydrogen; further, R 1 It is one of phenyl, substituted phenyl, thiophene ring, and pyridine ring; further, the substituent in the substituted phenyl is one of fluorine, chlorine, bromine, methyl, methoxy, and trifluoromethyl, and the substituent position is ortho, meta, or para of the amide group on the benzene ring.

[0016] Furthermore, the unsaturated amide is one of a primary amide, a secondary amide, or a tertiary amide.

[0017] Furthermore, the molar ratio of the unsaturated amide compound to the reducing agent and zinc catalyst used is 1:(1.7~2.3):(0.05~0.12).

[0018] Furthermore, the reducing agent is benzylsilane.

[0019] Furthermore, the reaction solvent is isopropyl ether or toluene.

[0020] Furthermore, the reaction was carried out at a temperature of 80°C for 4 hours.

[0021] Further, the post-treatment involves adding a 30% KOH aqueous solution to the reaction solution to quench it, followed by centrifugation to separate the layers, and taking the organic phase layer; then extracting the aqueous phase three times with dichloromethane, combining the extracted dichloromethane with the organic layer, and finally removing the solvent by vacuum distillation.

[0022] Compared with the prior art, the present invention has the following advantages:

[0023] (1) The present invention utilizes inexpensive zinc carboxylate salts and inexpensive amine ligands to coordinate and synthesize zinc catalysts. The preparation steps are simple, the cost is low, and the catalyst has good stability. Compared with existing precious metal catalysts, the cost is significantly reduced, and it is more stable than existing inexpensive metal catalysts (such as iron and cobalt catalysts). It can also maintain good stability in an air atmosphere.

[0024] (2) The present invention is simple to operate, the experimental conditions are mild, and the reaction can be carried out in an air atmosphere without the need for inert gas atmosphere protection. Compared with the existing process, the reaction time is greatly shortened.

[0025] (3) The present invention can achieve the selective reduction of unsaturated amides to prepare unsaturated amine compounds under mild reaction conditions, and the synthesized unsaturated amine products have high yields, good functional group tolerance, and a wide range of substrate applicability. It can also selectively reduce primary amine compounds with high yields to highly challenging substrates such as primary amides. Attached Figure Description

[0026] Figure 1 The tetramethylethylenediamine dioctanoate zinc prepared in Example 1 1 H NMR spectrum.

[0027] Figure 2 The tetramethylethylenediamine dioctanoate zinc prepared in Example 1 13 C NMR spectrum. Detailed Implementation

[0028] A method for selectively reducing unsaturated amides with zinc catalysis to prepare unsaturated amines involves mixing an unsaturated amide compound, a reducing agent benzyl silane, and a zinc catalyst in a molar ratio of 1:(1.7~2.3):(0.05~0.12) with a reaction solvent of isopropyl ether or toluene under a nitrogen or air atmosphere. After reacting at 80°C for 4 h, the reaction solution is quenched with a 30% KOH aqueous solution. The mixture is then centrifuged to separate the layers, and the organic phase is collected. The aqueous phase is extracted three times with dichloromethane. The extracted dichloromethane is then combined with the organic phase, and the solvent is removed by vacuum distillation to obtain the corresponding unsaturated amine product.

[0029] The zinc catalyst is prepared by stirring zinc carboxylate, amine ligand, and isopropyl ether in a molar ratio of 1:1 at room temperature for 4 hours, followed by solvent removal under vacuum. Its general structural formula is: Where n = 1~8, X = 0 or N.

[0030] To make the content of this invention easier to understand, the technical solution of this invention will be further described below with reference to specific embodiments, but this invention is not limited thereto.

[0031] The reagents and other materials used in this invention are all commercially available products well known to those skilled in the art and can be obtained from commercial sources.

[0032] The analytical methods and the methods for calculating the yield of unsaturated amine products in the examples are as follows:

[0033] Qualitative analysis of gas chromatography-mass spectrometry (GC-MS) was performed using a Shimadzu GC-MSQP2020 NX system equipped with a Stbilwax capillary column (30.0 m × 0.25 mm × 0.25 μm). Quantitative analysis was performed using a GC-2014C GC equipped with a DB-5MS column (30 m × 0.25 mm × 0.25 μm) and a flame ionization detector (FID). Dioxane was used as an internal standard, and the yield of unsaturated amine products was quantitatively determined using the internal standard method.

[0034] .

[0035] Example 1: Preparation of zinc tetramethylethylenediamine dioctanoate (a)

[0036] Zinc octanoate (14.0704 g, 40 mmol), tetramethylethylenediamine (4.6484 g, 40 mmol), and isopropyl ether (200 mL) were added to a 250 mL flask. After stirring at room temperature for 4 h, the solvent was removed under vacuum to obtain 18.4427 g of molten solid, which was zinc dioctanoate of tetramethylethylenediamine, with a yield of 98.53%.

[0037] The catalyst has a melting point of 34.3℃. Elemental analysis (tetramethylethylenediamine dioctanoate zinc, C...) 22 H 46 (N2O4Zn): Theoretical values: C 56.46%; H 9.91%; N 5.99%; O 13.67%; Zn 13.97%; Measured values: C 56.39%; H 9.80%; N 6.12%; O 13.72%; Zn 14.13%. 1 H NMR (500 MHz, CDCl3): δ 2.69 (s, 4H), 2.52 (s, 10H), 2.36~2.22 (m, 4H), 1.61 (p, J =7.7 Hz, 4H), 1.34~1.17(m, 16H), 0.87 (d, J =14.0 Hz, 6H); 13 C NMR (CDCl3) δ 183.22, 77.37, 77.11, 76.86, 56.64, 46.57,35.58, 46.57, 35.58, 31.86, 29.61, 29.18,26.33, 22.72, 14.17.

[0038] Example 2: Preparation of zinc dioctanoate of N,N-dimethylethanolamine (b)

[0039] Zinc octanoate (14.0704 g, 40 mmol), N,N-dimethylethanolamine (3.5656 g, 40 mmol), and isopropyl ether (200 mL) were added to a 250 mL round-bottom flask. After stirring at room temperature for 4 h, the solvent was removed under vacuum to obtain 17.5508 g of the product N,N-dimethylethanolamine dioctanoate zinc, with a yield of 93.40%.

[0040] Example 3: Preparation of zinc tetramethylethylenediamine didiethylacetic acid (c)

[0041] Zinc diethylacetate (11.2664 g, 40 mmol), tetramethylethylenediamine (4.6484 g, 40 mmol), and isopropyl ether (200 mL) were added to a 250 mL flask. After stirring at room temperature for 4 h, the solvent was removed under vacuum to obtain 14.6713 g of the product, tetramethylethylenediamine di-diethylacetate zinc, with a yield of 92.19%.

[0042] Example 4:

[0043] In an air atmosphere, the catalyst N,N-dimethylethanolamine dioctanoate zinc (0.1174 g, 0.25 mmol), the substrate p-fluorobenzamide (0.3478 g, 2.5 mmol), phenylsilane (denoted as PhSiH3, 0.568 g, 5.25 mmol), and 1 mL of isopropyl ether were added sequentially to a reaction tube. The reaction was carried out in a water bath at 80 °C for 4 h. After the reaction was completed, 1 g of the reaction solution was quenched with 3 mL of 30% KOH aqueous solution, centrifuged to separate the layers, and the organic phase was collected. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the internal standard dioxane was added for gas chromatography analysis. The results showed that the yield of p-fluorobenzamide was 34.79%.

[0044] Example 5:

[0045] In an air atmosphere, the catalyst tetramethylethylenediamine di(diethylacetic acid) zinc (0.0995 g, 0.25 mmol), the substrate p-fluorobenzamide (0.3478 g, 2.5 mmol), phenylsilane (denoted as PhSiH3, 0.568 g, 5.25 mmol), and 1 mL of isopropyl ether were added sequentially to a reaction tube. The reaction was carried out in an 80 °C water bath for 4 h. After the reaction was completed, 1 g of the reaction solution was quenched with 3 mL of 30% KOH aqueous solution, centrifuged to separate the layers, and the organic phase was collected. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the internal standard dioxane was added for gas chromatography analysis. The results showed that the yield of p-fluorobenzamide was 26.90%.

[0046] Example 6:

[0047] In an air atmosphere, the catalyst tetramethylethylenediamine dioctanoate zinc (denoted as Zn(Oct)2(TEMED), 0.1173 g, 0.25 mmol), the substrate p-fluorobenzamide (0.3478 g, 2.5 mmol), phenylsilane (denoted as PhSiH3, 0.568 g, 5.25 mmol), and 1 mL of isopropyl ether were added sequentially to a reaction tube. The reaction was carried out in a water bath at 80 °C for 4 h. After the reaction was completed, 1 g of the reaction solution was quenched with 3 mL of 30% KOH aqueous solution, centrifuged to separate the layers, and the organic phase was collected. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the internal standard dioxane was added for gas chromatography analysis. The results showed that the yield of p-fluorobenzylamine was 72.79%.

[0048] Example 7:

[0049] In an air atmosphere, the catalyst tetramethylethylenediamine dioctanoate zinc (denoted as Zn(Oct)2(TEMED), 0.0704 g, 0.15 mmol), the substrate p-fluorobenzamide (0.3478 g, 2.5 mmol), phenylsilane (denoted as PhSiH3, 0.568 g, 5.25 mmol), and 1 mL of isopropyl ether were added sequentially to a reaction tube. The reaction was carried out in a water bath at 80 °C for 4 h. After the reaction was completed, 1 g of the reaction solution was quenched with 3 mL of 30% KOH aqueous solution, centrifuged to separate the layers, and the organic phase was collected. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the internal standard dioxane was added for gas chromatography analysis. The results showed that the yield of p-fluorobenzylamine was 50.78%.

[0050] Example 8:

[0051] In an air atmosphere, the catalyst tetramethylethylenediamine dioctanoate zinc (denoted as Zn(Oct)2(TEMED), 0.0939 g, 0.2 mmol), the substrate p-fluorobenzamide (0.3478 g, 2.5 mmol), phenylsilane (denoted as PhSiH3, 0.568 g, 5.25 mmol) and 1 mL isopropyl ether were added sequentially to a reaction tube. The reaction was carried out in an 80 °C water bath for 4 h. After the reaction was completed, 1 g of the reaction solution was quenched with 3 mL of 30% KOH aqueous solution, centrifuged to separate the layers, and the organic phase was collected. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the internal standard dioxane was added for gas chromatography analysis. The results showed that the yield of p-fluorobenzylamine was 72.88%.

[0052] Example 9:

[0053] In an air atmosphere, the catalyst tetramethylethylenediamine dioctanoate zinc (denoted as Zn(Oct)2(TEMED), 0.0939 g, 0.2 mmol), the substrate p-fluorobenzamide (0.3478 g, 2.5 mmol), phenylsilane (denoted as PhSiH3, 0.4598 g, 4.25 mmol), and 1 mL of isopropyl ether were added sequentially to a reaction tube. The reaction was carried out in a water bath at 80 °C for 4 h. After the reaction was completed, 1 g of the reaction solution was quenched with 3 mL of 30% KOH aqueous solution, centrifuged to separate the layers, and the organic phase was collected. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the internal standard dioxane was added for gas chromatography analysis. The results showed that the yield of p-fluorobenzamide was 68.61%.

[0054] Example 10:

[0055] In an air atmosphere, the catalyst tetramethylethylenediamine dioctanoate zinc (denoted as Zn(Oct)2(TEMED), 0.0939 g, 0.2 mmol), the substrate p-fluorobenzamide (0.3478 g, 2.5 mmol), phenylsilane (denoted as PhSiH3, 0.5139 g, 4.75 mmol) and 1 mL isopropyl ether were added sequentially to a reaction tube. The reaction was carried out in a water bath at 80 °C for 4 h. After the reaction was completed, 1 g of the reaction solution was quenched with 3 mL of 30% KOH aqueous solution. The mixture was centrifuged to separate the layers, and the organic phase was collected. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the internal standard dioxane was added for gas chromatography analysis. The results showed that the yield of p-fluorobenzylamine was 72.74%.

[0056] Example 11:

[0057] Under a nitrogen atmosphere, the catalyst tetramethylethylenediamine dioctanoate zinc (denoted as Zn(Oct)2(TEMED), 0.0939 g, 0.2 mmol), the substrate p-fluorobenzamide (0.3478 g, 2.5 mmol), phenylsilane (denoted as PhSiH3, 0.5680 g, 5.25 mmol), and 1 mL of isopropyl ether were added sequentially to a reaction tube. The reaction was carried out in a water bath at 80 °C for 4 h. After the reaction was completed, 1 g of the reaction solution was quenched with 3 mL of 30% KOH aqueous solution, centrifuged to separate the layers, and the organic phase was collected. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and the internal standard dioxane was added for gas chromatography analysis. The results showed that the yield of p-fluorobenzylamine was 70.56%.

[0058] Various unsaturated amide compounds were reduced under the conditions described in Example 10, and the results are shown in Table 1.

[0059] Table 1. Selective reduction reactions of different unsaturated amide compounds

[0060]

[0061] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. Use of a zinc catalyst in the catalytic selective reduction of an unsaturated amide to produce an unsaturated amine, characterized in that, The zinc catalyst is any one of the following formulas (a)-(c): ； The application method involves mixing unsaturated amide compounds, reducing agents, and zinc catalysts in a reaction solvent under a nitrogen or air atmosphere, followed by post-treatment of the reaction solution to obtain the corresponding unsaturated amine.

2. Use according to claim 1, characterized in that, The zinc catalyst was prepared by stirring zinc carboxylate, amine ligand and solvent isopropyl ether at room temperature for 4 h, and then removing the solvent under vacuum. The molar ratio of zinc carboxylate salt to amine ligand used is 1:

1.

3. The application according to claim 2, characterized in that, The zinc carboxylate salt contains C2 to C9 carbon atoms; the amine ligand is tetramethylethylenediamine or N,N-dimethylethanolamine.

4. The application according to claim 1, characterized in that, The unsaturated amide is one of a primary amide, a secondary amide, or a tertiary amide.

5. The application according to claim 1, characterized in that, The molar ratio of the unsaturated amide compound used to the reducing agent and zinc catalyst is 1:(1.7~2.3):(0.05~0.12).

6. The application according to claim 1, characterized in that, The reducing agent is benzylsilane.

7. The application according to claim 1, characterized in that, The reaction solvent is isopropyl ether or toluene.

8. The application according to claim 1, characterized in that, The reaction was carried out at a temperature of 80°C for 4 hours.

9. The application according to claim 1, characterized in that, The post-treatment involves adding a 30% KOH aqueous solution to the reaction solution for quenching, followed by centrifugation to separate the layers, taking the organic phase, and extracting the aqueous phase three times with dichloromethane. The extracted dichloromethane is then combined with the organic phase, and the solvent is removed by vacuum distillation.

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