Method for synthesizing 2, 3-diphenyl propionitrile compound from benzyl cyanide compound through one-step method

Abstract

The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a method for synthesizing a 2, 3-diphenyl propionitrile compound from a phenylacetonitrile compound through a one-step method. Under the action of Cu (I) / ETS-10, the benzyl cyanide compound is used as a substrate for one-step synthesis of the 2, 3-diphenyl propionitrile compound, and the C-C coupling reaction of the benzyl cyanide compound is realized. The synthesis method is simple in condition, a target product can be efficiently synthesized without adding a complex noble metal complex as a catalyst, and valuable reference is provided for C-C coupling reaction of aromatic nitrile compounds.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthetic chemistry, and specifically relates to a reaction for synthesizing 2,3-diphenylpropionitrile compounds in one step by taking benzyl cyanide compounds as substrates under the action of Cu(I) / ETS-10. Background Art

[0002] Due to the wide application of nitrile compounds in the fields of pharmaceuticals and fine chemicals, it is becoming increasingly important to develop an efficient method for synthesizing nitrile compounds. In particular, pharmaceutical intermediates synthesized from 2,3-diphenylpropionitrile as a raw material have a high utilization value. At present, the most commonly used method for generating 2,3-diphenylpropionitrile is to construct a CC bond by a hydrogen transfer strategy with a transition metal catalyst. This method uses benzyl alcohol as an easily available alkylating agent to obtain 2,3-diphenylpropionitrile through a three-step reaction of dehydrogenation, coupling, and hydrogenation. The advantage of this method is that it avoids using alkyl halides as the raw materials for the reaction and water as the by-product of the reaction, thus reducing the generation of a large amount of waste. However, the only drawback is that most suitable catalytic systems are homogeneous catalytic systems, which require precious metal catalysts and special ligands, including precious metals such as Ru, Rh, Pd and Pt, which are very expensive, and the by-product water of the reaction may also cause the 2,3-diphenylpropionitrile functional group to hydrolyze into the corresponding amide, thereby forming a mixture, which makes the separation and purification of the product very difficult.

[0003] Therefore, in order to overcome these difficulties, non-precious metal catalysts are used in CC coupling reactions due to their low cost, but the reaction usually requires high metal loading or higher temperature, and it is inevitable to add special ligands to improve the efficiency of the reaction. Moreover, most catalysts are homogeneous catalysts and cannot be reused. At the same time, the catalysts have very poor catalytic effects on aromatic nitrile compounds with groups on the benzene ring. Obviously, there are still some unfinished challenges in the CC coupling reaction of nitrile compounds: (1) the development of efficient heterogeneous catalysts based on non-precious metals; (2) the use of aromatic nitrile compounds with groups for CC coupling reactions. Therefore, the development of effective catalysts to overcome these difficulties remains a fruitful but challenging task. Summary of the invention

[0004] The present invention realizes the CC coupling reaction of benzyl cyanide compounds under the action of Cu(I) / ETS-10 to synthesize 2,3-diphenylpropionitrile compounds. Cu(I) / ETS-10 has good stability, low price, economic value, and good product yield.

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

[0006] With benzyl cyanide compounds as reaction raw materials, a quantitative amount of Cu(I) / ETS-10, a base, benzyl cyanide compounds and a solvent are added into a reaction device, and the reaction is carried out at a set temperature. Then, the generated mixture is centrifuged and rotary evaporated, and the obtained liquid product is separated by column chromatography to obtain pure 2,3-diphenylpropionitrile compounds.

[0007] The reaction structure is as follows:

[0008]

[0009] R is selected from one of hydrogen, alkyl, alkoxy and halo.

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

[0011] 4-Fluoro.

[0012] The reaction temperature in the present invention is 100-140° C. The reaction time is 6-24 hours. 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 benzyl cyanide 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 the molar ratio of the benzyl cyanide 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 commercially available or homemade.

[0018] Furthermore, the preparation method of Cu(I) / ETS-10 is as follows: weigh ETS-10 zeolite and add distilled water, add cuprous iodide after ultrasonic treatment, stir in an oil bath at 80-100°C for 5-8h, then use a rotary evaporator to evaporate the water in the flask, and finally put it in an oven at 50-80°C for drying for 24-36h 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 efficiently synthesized without adding complex precious 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. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0023] Figure 2 The gas phase mass spectrum of the product of Example 1 is shown in FIG.

[0024] Figure 3 The gas phase mass spectrum of the product of Example 2 is shown in FIG.

[0025] Figure 4 The gas phase mass spectrum of the product of Example 3 is shown in FIG.

[0026] Figure 5 The gas phase mass spectrum of the product of Example 4 is shown in FIG.

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

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

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

[0030] Fig. 9 This is the gas phase mass spectrum of the product of Example 8. DETAILED DESCRIPTION

[0031] In order to further understand the content, purpose and advantages of the present invention, the specific embodiments of the present invention are now described in detail, but the reaction conditions should be changed according to the actual situation and should not be limited to the following examples. 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 hydrothermal method. The typical synthesis process is as follows: weigh 2.784g of anhydrous KF and put it into a beaker, then add 25.0mL of deionized water, stir for 20-30min, then add 12.8g of titanium trichloride, stir for 30min, and obtain a titanium-containing solution. Weigh 3.2g of NaOH and put it into a beaker, add 20mL of deionized water, stir for 20min, measure 19.5mL of water glass and add it, stir for 30min, and obtain an alkaline clear solution. The titanium-containing solution obtained above is added dropwise to the alkaline solution, and the system is stirred for 3-4h. The gel composition of the system is 1.0TiO2:8.0SiO2:5.2Na2O:3.4KF:242H2O. Crystallize at 200℃ for three days. After the crystallization, the suspension was washed several times with deionized water until it was neutral, filtered, dried, and finally calcined at 450°C for 3h to obtain ETS-10 zeolite.

[0033] Synthesis method of Cu(I) / ETS-10: Synthesis method of Cu(I) / ETS-10: Weigh 1 g of ETS-10 zeolite and put it into a round-bottom flask, add 50 ml of distilled water into the beaker, ultrasonicate for 5 minutes, then weigh 0.1729 g of cuprous iodide and put it into the round-bottom flask, stir in an 80°C oil bath for 5 hours, then use a rotary evaporator to evaporate the water in the flask, and finally put it into an oven at 50°C and dry for 24 hours to obtain Cu(I) / ETS-10, which is used in the following examples.

[0034] Embodiment 1:

[0035]

[0036] 30 mg of Cu(I) / ETS-10 catalyst, 0.4 mmol of KOH, 0.2 mmol of benzyl cyanide and 1 mL of N,N-dimethylformamide were added to the reaction tube. The reaction was carried out in an air atmosphere at 130°C for 14 h in the reactor, and then cooled to room temperature. The obtained reaction solution was centrifuged and sampled. The conversion rate and selectivity were determined by GC. The final calculated yield of 2,3-diphenylpropionitrile was 95.9%. The reaction solution was rotary evaporated and then separated by column chromatography (eluting reagent was a mixture of ethyl acetate and petroleum ether) to obtain the product. Example 1 Product 1 H NMR spectrum: 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: Based on the conditions of Example 1 above, the effect of reaction temperature on product yield was studied, 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: Based on the conditions of Example 1 above, the effect of reaction time on product yield was studied, 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: Based on the conditions of Example 1 above, the effect of Cu(I) / ETS-10 mass on product yield was studied, with other conditions unchanged.

[0044] Table 3

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

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

[0047] Table 4

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

[0049] Study on the effect of reaction atmosphere: If the reaction atmosphere in Example 1 is changed to nitrogen, and other conditions remain unchanged, the conversion rate and selectivity are measured by GC, and the yield of the product is 31.7%.

[0050] Embodiment 2:

[0051]

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

[0053] Embodiment 3:

[0054]

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

[0056] Embodiment 4:

[0057]

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

[0059] Embodiment 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 the reaction tube, and the reaction was carried out in a reactor at 130° C. under an air atmosphere for 14 hours. The reaction mixture was then cooled to room temperature and the obtained reaction solution was centrifuged and sampled. The conversion rate and selectivity were determined by GC. The final calculated yield of 2,3-di-p-methoxyphenylpropionitrile was 71.9%. The reaction solution was rotary evaporated and then separated by column chromatography (eluting reagent was a mixture of ethyl acetate and petroleum ether) to obtain the product.

[0062] Embodiment 6:

[0063]

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

[0065] Embodiment 7:

[0066]

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

[0068] Embodiment 8:

[0069]

[0070] 30 mg of Cu(I) / ETS-10 catalyst, 0.4 mmol of KOH, 0.2 mmol of 4-fluorobenzeneacetonitrile and 1 mL of N,N-dimethylformamide were added to the reaction tube, and the reaction was carried out in a reactor at 130° C. under an air atmosphere for 14 hours. The reaction mixture was then cooled to room temperature and the obtained reaction solution was centrifuged and sampled. The conversion rate and selectivity were determined by GC. The final calculated yield of 2,3-di-p-fluorophenylpropionitrile was 70.3%. The reaction solution was rotary evaporated and then 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 benzyl cyanide and 1 mL of N,N-dimethylformamide were added to the reaction tube, and the reaction was carried out in the reactor at 130°C under air atmosphere for 14 h, then cooled to room temperature, and then the obtained reaction solution was centrifuged and sampled, and the conversion rate and selectivity were determined by GC. The final calculated yield of 2,3-diphenylpropionitrile was 0.8%, and the reaction solution was rotary evaporated and then separated by column chromatography (eluting reagent was a mixture of ethyl acetate and petroleum ether) to obtain the product. Comparative Example 2:

[0073] Add 30 mg of Cu(I) / ETS-10, 0.4 mmol of Cs2CO3, 0.2 mmol of benzyl cyanide and 1 mL of N,N-dimethylformamide into a reaction tube, react in an air atmosphere at 130°C in a reactor for 14 h, then cool to room temperature, and then centrifuge the obtained reaction solution and take a sample. The conversion rate and selectivity are determined by GC, and the final calculated yield of 2,3-diphenylpropionitrile is 4.1%. After rotary evaporation of the reaction solution, column chromatography (eluting reagent is a mixture of ethyl acetate and petroleum ether) is performed to separate the product.

[0074] Comparative Example 3:

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

[0076] 30 mg of Cu(I) / ETS-10, 0.4 mmol of KOH, 0.2 mmol of benzyl cyanide and 1 mL of N,N-dimethylformamide were added to the reaction tube, and the reaction was carried out in a reactor at 130°C under an oxygen atmosphere for 14 hours. The reaction mixture was then cooled to room temperature and centrifuged to take a sample. The conversion rate and selectivity were determined by GC. It was finally calculated that no 2,3-diphenylpropionitrile was generated. The reaction mixture was rotary evaporated and then separated by column chromatography (eluting reagent was a mixture of ethyl acetate and petroleum ether) to obtain the product.

[0077] Comparative Example 5:

[0078] The synthesis method of Cu(II) / ETS-10 is as follows: copper nitrate trihydrate is weighed in water, the copper nitrate trihydrate solid is uniformly dispersed by ultrasound, an equal volume of the mixed solution is impregnated on an ETS-10 carrier, the catalyst is naturally dried, and then calcined in a muffle furnace at 350-400°C for 3-4h to prepare a Cu(II) / ETS-10 catalyst, wherein the loading mass of Cu(II) on ETS-10 is 5%.

[0079] Add 30 mg of Cu(II) / ETS-10, 0.4 mmol of KOH, 0.2 mmol of benzyl cyanide and 1 mL of N,N-dimethylformamide to the reaction tube, react in the reactor at 130°C under air atmosphere for 14 hours, then cool to room temperature, and then centrifuge the obtained reaction solution and take a sample, use GC to determine the conversion rate and selectivity, and finally calculate that no 2,3-diphenylpropionitrile is generated. After rotary evaporation of the reaction solution, column chromatography (eluting reagent is a mixture of ethyl acetate and petroleum ether) is performed to separate the product.

[0080] Comparative Example 6:

[0081] Add 30 mg of 5% Cu(I) / ZSM-5, 0.4 mmol of KOH, 0.2 mmol of benzyl cyanide and 1 mL of N,N-dimethylformamide to the reaction tube, react in the reactor at 130°C under air atmosphere for 14 h, then cool to room temperature, and then centrifuge the obtained reaction solution and take a sample, use GC to determine the conversion rate and selectivity, and finally calculate that the yield of 2,3-diphenylpropionitrile is 0.24%. After rotary evaporation of the reaction solution, column chromatography (eluting reagent is a mixture of ethyl acetate and petroleum ether) is performed to separate the product.

[0082] Comparative Example 7:

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

[0084] Comparative Example 8:

[0085] Add 30 mg of 5% Co / ETS-10, 0.4 mmol of KOH, 0.2 mmol of benzyl cyanide and 1 mL of N,N-dimethylformamide to the reaction tube, react in the reactor at 130°C under air atmosphere for 14 hours, then cool to room temperature, and then centrifuge the obtained reaction solution and take a sample, use GC to determine the conversion rate and selectivity, and finally calculate that no 2,3-diphenylpropionitrile is generated. After rotary evaporation of the reaction solution, column chromatography (elution reagent is a mixture of ethyl acetate and petroleum ether) is performed to separate 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 rate and selectivity are determined by GC, and it is finally concluded that no 2,3-diphenylpropionitrile is generated.

Claims

1. A method for synthesizing 2,3-diphenylpropionitrile compounds from benzyl cyanide compounds in one step, characterized in that: Using benzyl cyanide compounds as reaction raw materials, adding solvent, Cu(I) / ETS-10 catalyst and base into a reaction device, reacting under heating conditions, centrifuging and rotary evaporating the reaction mixture, and separating the obtained liquid product by column chromatography to obtain 2,3-diphenylpropionitrile compounds; 2. The method for synthesizing 2,3-diphenylpropionitrile compounds from benzyl cyanide compounds in one step according to claim 1, characterized in that: R is selected from one or more of hydrogen, alkyl, alkoxy and halo.

3. The method for synthesizing 2,3-diphenylpropionitrile compounds from benzyl cyanide compounds in one step according to claim 1, characterized in that: The heating conditions are 100-140°C and the reaction time is 6-24h.

4. The method for synthesizing 2,3-diphenylpropionitrile compounds from benzyl cyanide compounds in one step according to claim 1, characterized in that: The copper valence in Cu(I) / ETS-10 is 1; the preparation method of Cu(I) / ETS-10 is as follows: weigh ETS-10 zeolite and add distilled water, add cuprous iodide after ultrasonication, stir in an 80-100°C oil bath for 5-8h, then use a rotary evaporator to evaporate the water in the flask, and finally put it into an oven at 50-80°C for drying for 24-36h to obtain Cu(I) / ETS-10.

5. The method for synthesizing 2,3-diphenylpropionitrile compounds from benzyl cyanide compounds in one step according to claim 1, characterized in that: The reaction atmosphere is air or nitrogen.

6. The method for synthesizing 2,3-diphenylpropionitrile compounds from benzyl cyanide compounds in one step according to claim 1, characterized in that: The base is KOH, and the ratio of the molar amount of the base to the molar amount of the benzyl cyanide compound is 1:1 to 3:

1.

7. The method for synthesizing 2,3-diphenylpropionitrile compounds from benzyl cyanide compounds in one step according to claim 1, characterized in that: The reaction solvent is N,N-dimethylformamide.

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

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