One-step synthesis of 2,3-diphenylpropionitriles from phenylacetonitriles

Abstract

The application belongs to the technical field of organic synthesis chemistry, and particularly relates to a method for synthesizing 2,3-diphenylpropionitrile compounds from benzyl cyanide compounds in one step. The application realizes C-C coupling reaction of benzyl cyanide compounds by synthesizing 2,3-diphenylpropionitrile compounds from benzyl cyanide compounds as substrates in one step under the action of Cu(I) / ETS-10. The synthesis method has simple conditions, and the target product can be efficiently synthesized without adding a complex noble metal complex as a catalyst, thereby providing a valuable reference for C-C coupling reaction of aromatic nitrile compounds.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis chemistry technology, specifically relating to the one-step synthesis of 2,3-diphenylpropionitrile compounds using phenylacetonitrile compounds as substrates under the action of Cu(I) / ETS-10. Background Technology

[0002] Due to the widespread application of nitrile compounds in pharmaceuticals and fine chemicals, developing efficient methods for their synthesis has become increasingly important. In particular, pharmaceutical intermediates synthesized from 2,3-diphenylpropionitrile have high utilization value. Currently, the most common method for generating 2,3-diphenylpropionitrile is a hydrogen transfer strategy using transition metal catalysts to construct C-C bonds. This method uses benzyl alcohol as an readily available alkylating agent, and 2,3-diphenylpropionitrile is obtained through a three-step reaction involving dehydrogenation, coupling, and hydrogenation. The advantage of this method is that it avoids using alkyl halides as reactants and water as a byproduct, reducing the generation of significant waste. However, the only drawback is that most suitable catalytic systems are homogeneous, requiring noble metal catalysts and special ligands, including Ru, Rh, Pd, and Pt, which are very costly. Furthermore, the byproduct water can cause the functional groups of 2,3-diphenylpropionitrile to hydrolyze into the corresponding amides, forming a mixture, which makes product separation and purification very difficult.

[0003] Therefore, to overcome these difficulties, non-precious metal catalysts have been used in CC coupling reactions due to their low cost. However, the reactions usually require high metal loadings or higher temperatures, and the addition of special ligands is unavoidable to improve reaction efficiency. Moreover, most catalysts are homogeneous and cannot be reused. Furthermore, the catalysts are very ineffective for aromatic nitriles with functional groups on the benzene ring. Clearly, there are still some unresolved challenges in the CC coupling reactions of nitriles: (1) developing highly efficient heterogeneous catalysts based on non-precious metals; and (2) using aromatic nitriles with functional groups for CC coupling reactions. Therefore, developing effective catalysts to overcome these difficulties remains a fruitful but challenging task. Summary of the Invention

[0004] This invention achieves the CC coupling reaction of phenylacetonitrile compounds using Cu(I) / ETS-10 to synthesize 2,3-diphenylpropionitrile compounds. Cu(I) / ETS-10 exhibits good stability and is inexpensive, making it economically viable, and the product yield is good.

[0005] The technical solution of the present invention is as follows:

[0006] Using phenylacetonitrile compounds as reactants, a fixed amount of Cu(I) / ETS-10, alkali, phenylacetonitrile compounds and solvent were added to the reaction equipment. The reaction was carried out at a set temperature. The resulting mixture was then centrifuged and rotary evaporated. The resulting liquid product was then separated by column chromatography to obtain pure 2,3-diphenylpropionitrile compounds.

[0007] The reaction structure is as follows:

[0008]

[0009] R is derived from one of hydrogen, alkyl, alkoxy, or halogroup.

[0010] Furthermore, R is derived from hydrogen, 3-methyl, 4-methyl, 2-methoxy, 4-methoxy, 2-chloro, 4-chloro,

[0011] 4-Fluorine.

[0012] The reaction temperature in this invention is 100–140°C. The reaction time is 6–24 h. The reaction solvent is N,N-dimethylformamide. The reaction atmosphere is air and nitrogen, preferably air.

[0013] Furthermore, the ratio of the mass (mg) of Cu(I) / ETS-10 to the molar amount (mmol) of the phenylacetonitrile compound is 75:1 to 225:1, preferably 150:1 to 225:1.

[0014] Furthermore, the base is KOH.

[0015] Furthermore, the molar ratio of KOH to phenylacetonitrile compound is 1:1 to 3:1, preferably 2:1 to 3:1.

[0016] Furthermore, the solvent is N,N-dimethylformamide.

[0017] ETS-10 is available commercially or can be made at home.

[0018] Further, the preparation method of Cu(I) / ETS-10 is as follows: ETS-10 zeolite is weighed and added to distilled water, ultrasonicated, and then cuprous iodide is added. The mixture is stirred in an oil bath at 80-100℃ for 5-8 hours. Then, the water in the flask is evaporated using a rotary evaporator. Finally, the mixture is dried in an oven at 50-80℃ for 24-36 hours to obtain Cu(I) / ETS-10. The loading mass of Cu(I) on ETS-10 is 3-6%.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] (1) The conditions are simple and the target product can be synthesized efficiently without the need to add complex noble metal complexes as catalysts.

[0021] (2) The Cu(I) / ETS-10 catalyst is inexpensive, environmentally friendly and economical, and has economic value and industrial significance. Attached Figure Description

[0022] Figure 1 The product of Example 1 1 H-NMR spectrum.

[0023] Figure 2 This is the gas phase mass spectrum of the product from Example 1.

[0024] Figure 3 This is the gas phase mass spectrum of the product from Example 2.

[0025] Figure 4 This is the gas phase mass spectrum of the product of Example 3.

[0026] Figure 5 This is the gas phase mass spectrum of the product of Example 4.

[0027] Figure 6 This is the gas phase mass spectrum of the product from Example 5.

[0028] Figure 7 This is the gas phase mass spectrum of the product from Example 6.

[0029] Figure 8 This is the gas phase mass spectrum of the product from Example 7.

[0030] Figure 9 The image shows the gas phase mass spectrum of the product from Example 8. Detailed Implementation

[0031] To further understand the content, purpose, and advantages of this invention, specific embodiments are now described in detail. However, reaction conditions should be modified according to actual circumstances, and the invention should not be limited to the examples described below. Unless otherwise specified, the instruments and reagents used in the following examples are commercially available products.

[0032] Synthesis method of ETS-10: ETS-10 zeolite is synthesized by a hydrothermal method. A typical synthesis process is as follows: Weigh 2.784 g of anhydrous KF into a beaker, then add 25.0 mL of deionized water and stir for 20–30 min. Then add 12.8 g of titanium trichloride and stir for 30 min to obtain a titanium-containing solution. Weigh 3.2 g of NaOH into a beaker, add 20 mL of deionized water, and stir for 20 min. Measure 19.5 mL of water glass and add it, stirring for 30 min to obtain an alkaline clear solution. Add the titanium-containing solution obtained above dropwise to the alkaline solution, and stir the system for 3–4 h. The gel composition of the system is 1.0 TiO2:8.0 SiO2:5.2 Na2O:3.4 KF:242 H2O. Crystallize at 200 °C for three days. After crystallization, the suspension was washed multiple times with deionized water until neutral, filtered, dried, and finally calcined at 450℃ for 3 hours to obtain ETS-10 zeolite.

[0033] Synthesis method of Cu(I) / ETS-10: Weigh 1g of ETS-10 zeolite and put it into a round-bottom flask. Add 50ml of distilled water to the beaker and sonicate for 5min. Then weigh 0.1729g of cuprous iodide and put it into the round-bottom flask. Stir in an oil bath at 80℃ for 5h. Then evaporate the water in the flask using a rotary evaporator. Finally, dry in an oven at 50℃ for 24h to obtain Cu(I) / ETS-10, which is used in the following examples.

[0034] Example 1:

[0035]

[0036] 30 mg of Cu(I) / ETS-10 catalyst, 0.4 mmol of KOH, 0.2 mmol of phenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. Afterward, the temperature was lowered to room temperature, and the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. The yield of 2,3-diphenylpropionitrile was calculated to be 95.9%. The reaction solution was then rotary evaporated, followed by column chromatography (eluent: a mixture of ethyl acetate and petroleum ether) to separate the product. Example 1 Product 1 H-spectrum NMR: 1 HNMR(400MHz,Chloroform-d)δ7.30-7.18(m,8H),7.07(d,J=7.6Hz,2H),3.96-3.90(m,1H),3.13(dd,J=13.5,8.3Hz,1H),3.06(dd,J=13.6,6.5Hz,1H).

[0037] Table 1: The effect of reaction temperature on product yield was studied under the conditions of Example 1 above, with other conditions remaining unchanged.

[0038] Table 1

[0039] reaction temperature Product yield 120℃ 63.8％ 140℃ 99.5％ 150℃ 99.2％

[0040] Table 2: The effect of reaction time on product yield was studied under the conditions of Example 1 above, with other conditions remaining unchanged.

[0041] Table 2

[0042] reaction time Product yield 12h 74.6％ 13h 83.9％ 15h 96％ 17h 98％

[0043] Table 3: The effect of Cu(I) / ETS-10 mass on product yield was studied under the conditions of Example 1 above, with other conditions remaining unchanged.

[0044] Table 3

[0045] Cu(I) / ETS-10 mass Product yield 15mg 60.9％ 45mg 97.7％

[0046] Table 4: The effect of KOH molar amount on product yield was studied under the conditions of Example 1 above, with other conditions remaining unchanged.

[0047] Table 4

[0048] molar amount of KOH Product yield 0.2mmol 75.6％ 0.6mmol 97.8％

[0049] The effect of reaction atmosphere was investigated: if the reaction atmosphere in Example 1 was changed to nitrogen, while other conditions remained unchanged, the conversion and selectivity were determined by GC, and the yield of the product was 31.7%.

[0050] Example 2:

[0051]

[0052] 30 mg of Cu(I) / ETS-10 catalyst, 0.4 mmol of KOH, 0.2 mmol of 3-methylphenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. The yield of 2,3-di-m-methylphenylpropionitrile was calculated to be 96.2%. The reaction solution was then rotary evaporated and separated by column chromatography (using a mixture of ethyl acetate and petroleum ether as eluent) to obtain the product.

[0053] Example 3:

[0054]

[0055] 30 mg of Cu(I) / ETS-10 catalyst, 0.4 mmol of KOH, 0.2 mmol of 4-methylphenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. The yield of 2,3-di-p-methylphenylpropionitrile was calculated to be 91%. The reaction solution was then rotary evaporated and separated by column chromatography (using a mixture of ethyl acetate and petroleum ether as eluent) to obtain the product.

[0056] Example 4:

[0057]

[0058] 30 mg of Cu(I) / ETS-10 catalyst, 0.4 mmol of KOH, 0.2 mmol of 2-methoxyphenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. The yield of 2,3-di-o-methoxyphenylpropionitrile was calculated to be 71.7%. The reaction solution was then rotary evaporated and separated by column chromatography (eluting reagent was a mixture of ethyl acetate and petroleum ether) to obtain the product.

[0059] Example 5:

[0060]

[0061] 30 mg of Cu(I) / ETS-10 catalyst, 0.4 mmol of KOH, 0.2 mmol of 4-methoxyphenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. The yield of 2,3-di-p-methoxyphenylpropionitrile was calculated to be 71.9%. The reaction solution was then rotary evaporated and separated by column chromatography (eluting reagent was a mixture of ethyl acetate and petroleum ether) to obtain the product.

[0062] Example 6:

[0063]

[0064] 30 mg of Cu(I) / ETS-10 catalyst, 0.4 mmol of KOH, 0.2 mmol of 2-chlorophenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. The yield of 2,3-di-o-chlorophenylpropionitrile was calculated to be 81.5%. The reaction solution was then rotary evaporated and separated by column chromatography (using a mixture of ethyl acetate and petroleum ether as eluent) to obtain the product.

[0065] Example 7:

[0066]

[0067] 30 mg of Cu(I) / ETS-10 catalyst, 0.4 mmol of KOH, 0.2 mmol of 4-chlorophenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. The yield of 2,3-di-p-chlorophenylpropionitrile was calculated to be 83.4%. The reaction solution was then rotary evaporated and separated by column chromatography (using a mixture of ethyl acetate and petroleum ether as eluent) to obtain the product.

[0068] Example 8:

[0069]

[0070] 30 mg of Cu(I) / ETS-10 catalyst, 0.4 mmol of KOH, 0.2 mmol of 4-fluorophenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. The yield of 2,3-di-p-fluorophenylpropionitrile was calculated to be 70.3%. The reaction solution was then rotary evaporated and separated by column chromatography (eluting reagent was a mixture of ethyl acetate and petroleum ether) to obtain the product.

[0071] Comparative Example 1:

[0072] 30 mg of Cu(I) / ETS-10, 0.4 mmol of NaOH, 0.2 mmol of phenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. The yield of 2,3-diphenylpropionitrile was calculated to be 0.8%. The reaction solution was then rotary evaporated, followed by column chromatography (eluting reagent: a mixture of ethyl acetate and petroleum ether) to separate the product. Comparative Example 2:

[0073] 30 mg of Cu(I) / ETS-10, 0.4 mmol of Cs₂CO₃, 0.2 mmol of phenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. The yield of 2,3-diphenylpropionitrile was calculated to be 4.1%. The reaction solution was then rotary evaporated and separated by column chromatography (using a mixture of ethyl acetate and petroleum ether as eluent) to obtain the product.

[0074] Comparative Example 3:

[0075] 30 mg of Cu(I) / ETS-10, 0.4 mmol of K₂CO₃, 0.2 mmol of phenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. The yield of 2,3-diphenylpropionitrile was calculated to be 1.2%. The reaction solution was then rotary evaporated, followed by column chromatography (eluting reagent: a mixture of ethyl acetate and petroleum ether) to separate the product. Comparative Example 4:

[0076] 30 mg of Cu(I) / ETS-10, 0.4 mmol of KOH, 0.2 mmol of phenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under an oxygen atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. It was finally calculated that no 2,3-diphenylpropionitrile was formed. The reaction solution was then rotary evaporated and separated by column chromatography (using a mixture of ethyl acetate and petroleum ether as the eluent) to obtain the product.

[0077] Comparative Example 5:

[0078] Synthesis method of Cu(II) / ETS-10: Weigh copper nitrate trihydrate in water, disperse the copper nitrate trihydrate solid uniformly by ultrasonication, impregnate the mixture onto the ETS-10 support with an equal volume, let the catalyst air dry naturally, and then calcine it in a muffle furnace at 350-400℃ for 3-4 hours to prepare Cu(II) / ETS-10 catalyst, wherein the loading mass of Cu(II) on ETS-10 is 5%.

[0079] 30 mg of Cu(II) / ETS-10, 0.4 mmol of KOH, 0.2 mmol of phenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. It was finally calculated that no 2,3-diphenylpropionitrile was formed. The reaction solution was then rotary evaporated and separated by column chromatography (eluting reagent was a mixture of ethyl acetate and petroleum ether) to obtain the product.

[0080] Comparative Example 6:

[0081] 30 mg of 5% Cu(I) / ZSM-5, 0.4 mmol of KOH, 0.2 mmol of phenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. The yield of 2,3-diphenylpropionitrile was calculated to be 0.24%. The reaction solution was then rotary evaporated and separated by column chromatography (eluting reagent was a mixture of ethyl acetate and petroleum ether) to obtain the product.

[0082] Comparative Example 7:

[0083] 30 mg of 5% Cu(I) / Silicate, 0.4 mmol of KOH, 0.2 mmol of phenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. It was finally calculated that no 2,3-diphenylpropionitrile was formed. The reaction solution was then rotary evaporated and separated by column chromatography (eluting reagent was a mixture of ethyl acetate and petroleum ether) to obtain the product.

[0084] Comparative Example 8:

[0085] 30 mg of 5% Co / ETS-10, 0.4 mmol of KOH, 0.2 mmol of phenylacetonitrile, and 1 mL of N,N-dimethylformamide were added to a reaction tube. The reaction was carried out in a reactor at 130 °C for 14 h under air atmosphere. After cooling to room temperature, the resulting reaction solution was centrifuged and sampled. The conversion and selectivity were determined by GC. It was finally calculated that no 2,3-diphenylpropionitrile was formed. The reaction solution was then rotary evaporated and separated by column chromatography (eluting reagent was a mixture of ethyl acetate and petroleum ether) to obtain the product.

[0086] Comparative Example 9:

[0087] If the solvent in Example 1 is replaced with 1 mL of DMSO, and other conditions remain unchanged, the conversion and selectivity are determined by GC. Finally, it is found that no 2,3-diphenylpropionitrile is generated.

Claims

1. A method for synthesizing 2,3-diphenylpropionitrile compounds from phenylacetonitrile compounds in one step, characterized in that: The 2,3-diphenylpropionitrile compound is obtained by using phenylacetonitrile compound as a reaction raw material, adding a solvent, Cu(I) / ETS-10 catalyst and a base in a reaction device, reacting under heating, centrifuging, rotary evaporation, and column chromatography separation on the obtained liquid product. ； R is selected from one or more of hydrogen, alkyl, alkoxy, halogen; wherein the base is KOH; the reaction solvent is N , N dimethylformamide; the reaction atmosphere is air or nitrogen.

2. The method for synthesizing 2,3-diphenylpropionitrile compounds from phenylacetonitrile compounds according to claim 1, wherein: The heating condition is 100-140 DEG C, and the reaction time is 6-24 h.

3. The method for synthesizing 2,3-diphenylpropionitrile compounds in one step from phenylacetonitrile compounds according to claim 1, characterized in that: The copper valence of Cu(I) / ETS-10 is 1; the preparation method of Cu(I) / ETS-10 is: ETS-10 zeolite is weighed and added into distilled water, and after ultrasonic, cuprous iodide is added, and stirring is carried out under 80-100 DEG C oil bath for 5-8 h, then the water in the flask is evaporated by a rotary evaporator, and finally it is placed into a 50-80 DEG C oven for drying for 24-36 h to obtain Cu(I) / ETS-10.

4. The method for synthesizing 2,3-diphenylpropionitrile compounds from phenylacetonitrile compounds according to claim 1, wherein: The molar ratio of the base to the phenylacetonitrile compound is 1:1-3:

1.

5. The method for synthesizing 2,3-diphenylpropionitrile compounds in one step from phenylacetonitrile compounds according to claim 1, characterized in that: The mass ratio of Cu(I) / ETS-10 to the molar amount of the phenylacetonitrile compound is 75:1-225:1 mg / mmol.

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