A method for synthesizing triaryl acrylonitrile

Abstract

The invention discloses a synthetic method of triaryl acrylonitrile, which is prepared by reacting iodobenzene and benzyl cyanide as reactants; reactants are widely available and easy to prepare; the reaction of the present invention is carried out in a solvent, and the solvent is any one of n-hexane, methanol, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N-methylpyrrolidone, isopropanol and 1,2-dichloroethane, and the choice of solvent is very extensive; during the reaction, a palladium catalyst, a phosphorus ligand, an oxidant and a base are also added to the solvent; in the joint action of these several materials, it is possible to obtain an ideal product, and the reaction rate is relatively fast, and the yield is relatively high. The reaction temperature of the present invention is 110-180°C, and the reaction time is 24-50h, and the reaction conditions are very gentle, easily reachable, and safe; the yield reaches more than 75%, and a series of triaryl acrylonitrile can be prepared, and the method has a strong substrate universality, and provides a better guarantee for developing organic compounds related to triaryl acrylonitrile.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing triaryl acrylonitrile with diversified structures by reacting iodobenzene substances with benzyl cyanide substances under palladium catalysis. Background Art

[0002] Triarylaconitriles are of great significance in medicinal chemistry due to their biological activity and application in the synthesis of bioactive compounds. For example, some triarylaconitriles can inhibit the growth of certain tumors. In addition, triarylaconitriles also have comprehensive synthetic applications in organic and material chemistry. The earlier techniques for synthesizing triarylaconitriles include i) the reaction of diaryl ketones and benzyl cyanide, but the benzyl cyanide used in this method needs to be synthesized by highly toxic NaCN and HCN, etc.; ii) the reaction of diarylacetylene, aryl bromide and potassium hexacyanoferrate, in which diarylacetylene is usually synthesized from highly flammable acetylene gas that is difficult to handle. In recent years, the literature (Eur. J. Org. Chem. 2018, 1326–1332) reported a method for synthesizing triarylaconitriles in one pot with multiple components using calcium carbide as a simple acetylene source and K4[Fe(CN)6] as an environmentally friendly cyanide source, but this synthesis method has the disadvantages of low yield and poor functional group tolerance, and has certain limitations. Due to the existence of these defects, the practicability and applicability of these methods are greatly limited and cannot be truly promoted on a large scale. Summary of the invention

[0003] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for synthesizing triaryl acrylonitrile compounds with high selectivity and high yield from various substituted iodobenzenes and various substituted benzyl cyanides as raw materials, which has a wide source of raw materials and is simple to operate.

[0004] To achieve the above object, the present invention provides the following technical solutions:

[0005] A method for synthesizing triaryl acrylonitrile comprises: in the presence of an inert gas and a palladium catalyst, iodobenzene substances, benzyl cyanide substances, a phosphorus ligand, an oxidant, and a base are stirred and mixed in an organic solvent, and after the mixture is uniformly mixed, the mixture is heated for reaction to obtain triaryl acrylonitrile;

[0006] The structural formula of the iodobenzene substance is , wherein R1 is any one of methyl, methoxy and nitro;

[0007] The structural formula of the benzyl cyanide substance is , wherein R2 is any one of methyl, methoxy, and nitro;

[0008] The reaction formula is

[0009] .

[0010] As a further improvement of the present invention, the inert gas is any one of nitrogen, argon and helium.

[0011] As a further improvement of the present invention, the palladium catalyst is any one of bisacetonitrile palladium chloride, palladium trifluoroacetate, bis(triphenylphosphine)palladium chloride, tetrakis(triphenylphosphine)palladium, palladium acetate, palladium bromide and tris(dibenzylideneacetone)dipalladium.

[0012] As a further improvement of the present invention, the phosphorus ligand is any one of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, tricyclohexylphosphine, 4,5-bisdiphenylphosphine-9,9'-dimethylxanthene, 2-(dicyclohexylphosphine)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl and 2-(di-tert-butylphosphine)biphenyl.

[0013] As a further improvement of the present invention, the oxidant is any one of manganese dioxide, di-tert-butyl peroxide, hydrogen peroxide, oxygen and sodium hypochlorite.

[0014] As a further improvement of the present invention, the base is any one of sodium hydroxide, potassium hydroxide, potassium carbonate and cesium fluoride.

[0015] As a further improvement of the present invention, the organic solvent is any one of n-hexane, methanol, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, isopropanol and 1,2-dichloroethane.

[0016] As a further improvement of the present invention, during the reaction, the molar ratio of iodobenzene, benzyl cyanide, palladium catalyst, phosphorus ligand, oxidant and base is 1.0: 2.0-4.0: 0.05-0.15: 0.1-0.2: 0.15-0.4: 2-3.

[0017] As a further improvement of the present invention, the heating reaction specifically refers to reacting at a temperature of 110-180° C. for 24-50 hours.

[0018] When bisacetonitrile palladium chloride is used as a catalyst, 2-dicyclohexylphosphine-2'4'6'-triisopropylbiphenyl is a phosphorus ligand, manganese dioxide is an oxidant, sodium hydroxide is a base, and n-hexane is a solvent, the reaction formula is:

[0019] .

[0020] Beneficial effects of the present invention: Through in-depth and meticulous research, the present inventors have discovered a method for catalyzing the reaction of iodobenzene compounds and benzyl cyanide compounds under a bisacetonitrile palladium chloride catalytic system to achieve the synthesis of triaryl acrylonitrile with diverse structures. The method has a wide source of raw materials, is easy to operate, has wide universality, and has high selectivity. Compared with previous methods, the environmental protection and substrate universality are significantly improved, which is difficult to achieve with other methods. The present invention has the following advantages and innovations:

[0021] (1) The reaction has good universality and high yield, with most reactions having yields above 75%;

[0022] (2) This is an important supplement to the preparation of triaryl acrylonitrile compounds and provides an important idea for the synthesis of biologically active compounds;

[0023] (3) This method avoids the use of highly toxic cyanide compounds and highly flammable acetylene gas which is difficult to handle.

[0024] The triaryl acrylonitrile prepared by the method of the present invention has high quality, high yield, good reaction universality and convenient post-treatment; it realizes the direct construction of triaryl acrylonitrile compounds from various substituted iodobenzenes and substituted phenylacetonitrile, and provides an important reference for the construction of polyaryl olefin compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is the reaction mechanism diagram of the present invention; DETAILED DESCRIPTION Example 1

[0026] The preparation of 2,3,3-triphenylacrylonitrile has the following structural formula:

[0027]

[0028] Under nitrogen protection, raw materials iodobenzene (0.3 mmol), benzyl cyanide (0.9 mmol) and catalyst Pd(CH3CN)2Cl2 (10 mol%), xphos (15 mol%), MnO2 (30 mol%), and n-hexane (2.0 mL) were added and reacted at 150 °C for 48 h. The product separation yield was 86%.

[0029] 1 H NMR (500 MHz, CDCl3): δ 7.45-7.42 (m, 5H, ArH), 7.25-7.18 (m, 8H, ArH), 7.01 (d, J=7.8Hz, 2H, ArH). 13C NMR(125 MHz, CDCl3) δ 157.73, 140.38,139.04, 134.79, 130.74, 129.88, 129.83, 129.68, 128.94, 128.44, 128.42,128.32, 128.19, 120.08, 111.60. Example 2

[0030] Preparation of 2,3,3-tri-o-tolyl acrylonitrile, the structural formula is as follows:

[0031]

[0032] Under nitrogen protection, raw materials 2-methyliodobenzene (0.3 mmol), 2-methylbenzeneacetonitrile (0.9 mmol) and catalyst Pd(CH3CN)2Cl2 (10 mol%), xphos (15 mol%), MnO2 (30 mol%), and n-hexane (2.0 mL) were added, and the reaction was carried out at 150 °C for 48 h. The product separation yield was 75%.

[0033] 1 H NMR (500 MHz, CDCl3) δ 7.36-7.31 (m, 1H, ArH), 7.30 (d, J = 7.3 Hz, 1H, ArH), 7.25 (t, J=8.6Hz, 2H, ArH), 7.14-7.11 (m, 2H, ArH), 7.08 (t, J=7.5Hz, 1H, ArH), 6.99-6.94 (m, 4H, ArH), 6.90 (d, J=7.6Hz, 1H, ArH), 2.38 (s,3H, CH3), 2.33 (s, 3H, CH3), 1.93 (s, 3H, CH3). 13 C NMR (125 MHz, CDCl3) δ159.22, 139.22, 137.74, 136.61, 136.23, 136.14, 133.75, 131.05, 130.73,130.71, 130.67, 130.40, 130.17, 129.13, 128.70, 128.57, 125.86, 128.79,125.32, 118.57, 115.03, 20.27, 20.23, 20.18. Example 3

[0034] Preparation of 2,3,3-trimethylphenylacrylonitrile, the structural formula is as follows:

[0035]

[0036] Under nitrogen protection, raw materials 3-methyliodobenzene (0.3 mmol), 3-methylbenzeneacetonitrile (0.9 mmol) and catalyst Pd(CH3CN)2Cl2 (10 mol%), xphos (15 mol%), MnO2 (30 mol%), and n-hexane (2.0 mL) were added, and the reaction was carried out at 150 °C for 48 h. The product separation yield was 79%.

[0037] 1 H NMR (500 MHz, CDCl3) δ 7.32-7.28 (m, 1H, ArH), 7.25-7.23 (m, J = 6.0Hz, 3H, ArH), 7.13 (s, 1H, ArH), 7.05-7.02 (m, 4H, ArH), 6.96 (d, J=3.6 Hz,1H, ArH), 6.70 (s, 2H, ArH), 2.36 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.18 (s,3H, CH3). 13 C NMR(125 MHz, CDCl3) δ 157.90, 140.55, 139.07, 138.08, 138.03,137.77, 134.76, 131.17, 130.46, 130.31, 130.15, 129.59, 128.94, 128.25,128.10, 127.90, 127.78, 126.98, 126.80, 120.25, 111.44, 21.37, 21.27, 21.23. Example 4

[0038] Preparation of 2,3,3-tri-p-tolyl acrylonitrile, the structural formula is as follows:

[0039]

[0040] Under nitrogen protection, raw materials 4-methyliodobenzene (0.3 mmol), 4-methylbenzeneacetonitrile (0.9 mmol) and catalyst Pd(CH3CN)2Cl2 (10 mol%), xphos (15 mol%), MnO2 (30 mol%), and n-hexane (2.0 mL) were added, and the reaction was carried out at 150 °C for 48 h. The product separation yield was 82%.

[0041] 1 H NMR (500 MHz, CDCl3) δ 7.32 (d, J =7.9 Hz, 2H, ArH), 7.21-7.14 (m, 4H, ArH), 7.02-6.97 (m, 4H, ArH), 6.89 (d, J =8.1 Hz, 2H, ArH), 2.39 (s, 3H, CH3), 2.29 (s, 6H, CH3). 13 C NMR(125 MHz, CDCl3) δ 157.09, 139.86, 138.92, 138.04,137.95, 136.45, 132.22, 130.77, 129.92, 129.49, 129.09, 129.49, 128.84,120.59, 110.39, 21.39, 21.29, 21.20. Example 5

[0042] The preparation of 2,3,3-tri-p-methoxyphenyl acrylonitrile has the following structural formula:

[0043]

[0044] Under nitrogen protection, raw materials 4-methoxyiodobenzene (0.3 mmol), 4-methoxyphenylacetonitrile (0.9 mmol) and catalyst Pd(CH3CN)2Cl2 (10 mol%), xphos (15 mol%), MnO2 (30 mol%), and n-hexane (2.0 mL) were added, and the reaction was carried out at 150°C for 48 h. The product separation yield was 86%.

[0045] 1 H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 2.4 Hz, 1H, ArH), 7.97 (d, J = 2.1Hz, 1H, ArH), 7.85 (d, J = 9.0 Hz, 1H, ArH), 7.78 (d, J = 8.7 Hz, 1H, ArH),7.47 (s, 1H, ArH), 7.44 (d, J = 8.5 Hz, 2H, ArH), 7.24 (d, J = 2.7 Hz, 2H,ArH), 7.17 (dd, J= 9.0, 2.5 Hz, 1H, ArH), 7.03 (d, J = 8.5 Hz, 2H, ArH), 4.03(s, 3H, OCH3), 4.02 (s, 3H, OCH3), 3.90 (s, 3H, OCH3). 13 C NMR(125 MHz, CDCl3)δ 158.06, 157.88, 157.00, 151.03, 131.08, 130.01, 129.89, 128.48, 124.79,116.75, 115.99, 113.68, 109.99, 104.67, 104.25, 55.56, 55.52, 55.35. Example 6

[0046] Preparation of (Z)-2,3-diphenyl-3-(m-tolyl)acrylonitrile, the structural formula is as follows:

[0047]

[0048] Under nitrogen protection, raw materials 3-methyliodobenzene (0.3 mmol), benzyl cyanide (0.9 mmol) and catalyst Pd(CH3CN)2Cl2 (10 mol%), xphos (15 mol%), MnO2 (30 mol%), and n-hexane (2.0 mL) were added, and the reaction was carried out at 150 °C for 48 h. The product separation yield was 81%.

[0049] 1 H NMR (500 MHz, CDCl3): δ 7.46 – 7.43 (m, 4H, ArH), 7.25 – 7.20 (m, 6H, ArH), 7.07 (d, J = 4.8 Hz, 1H, ArH), 7.02 (d, J = 8.1 Hz, 2H, ArH), 6.79 (s,1H, ArH), 2.38 (s, 3H, CH3). 13 C NMR (125 MHz, CDCl3): δ157.94, 140.47, 139.07,138.10, 134.87, 131.26, 130.72, 129.86, 129.69, 129.63, 128.42, 128.38,128.24, 128.15, 127.02, 120.15, 111.44, 21.36. Example 7

[0050] Preparation of (Z)-3-(4-nitrophenyl)-2,3-diphenylacrylonitrile, the structural formula is as follows:

[0051]

[0052] Under nitrogen protection, raw materials 4-nitroiodobenzene (0.3 mmol), benzyl cyanide (0.9 mmol) and catalyst Pd(CH3CN)2Cl2 (10 mol%), xphos (15 mol%), MnO2 (30 mol%), and n-hexane (2.0 mL) were added, and the reaction was carried out at 150 °C for 48 h. The product separation yield was 83%.

[0053] 1 H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 8.4 Hz, 2H, ArH), 8.04 (d, J = 8.6Hz, 1H, ArH), 7.65 (d, J = 8.5 Hz, 2H, ArH), 7.27 (dd, J = 7.4, 4.9 Hz, 4H,ArH), 7.23 (d, J = 7.8 Hz, 3H, ArH), 6.97 (d, J = 7.8 Hz, 2H, ArH). 13 C NMR(125MHz, CDCl3) δ 154.87, 146.64, 137.87, 131.69, 130.87, 130.48, 129.66, 129.05,128.82, 128.65, 123.76, 123.45, 119.14, 118.32, 114.02.

[0054] Figure 1 It is the reaction mechanism diagram of the present invention:

[0055] Mechanism description: First, benzonitrile is deprotonated under the action of base to form carbon anion intermediate A, which then undergoes nucleophilic addition with another molecule of benzonitrile to obtain intermediate B. B is hydrolyzed to obtain intermediate C. C is then inserted with the intermediate obtained by oxidation addition of iodobenzene and palladium catalyst to obtain intermediate D. D undergoes β-carbon elimination to obtain intermediate E. E undergoes addition with aryl palladium species again to obtain intermediate F. F then eliminates a portion of water to obtain the target product.

[0056] A synthesis method of triaryl acrylonitrile of the present invention is prepared by reacting iodobenzene substances and benzyl cyanide substances as reactants; the reactants are widely available, easy to prepare, low in cost, and low in toxicity, and are not likely to affect human health. The reaction of the present invention is carried out in a solvent, and the solvent is any one of n-hexane, methanol, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, isopropanol and 1,2-dichloroethane, and the choice of solvent is very wide; during the reaction, a palladium catalyst, a phosphorus ligand, an oxidant and a base are also added to the solvent; under the joint action of these substances, an ideal product can be obtained, and the reaction rate is fast and the yield is high. The reaction temperature of the present invention is 110-180°C, the reaction time is 24-50h, and the reaction conditions are very mild, easy to achieve, and safe.

[0057] The method of the invention can directly synthesize the target product in one step without separating the intermediate product. The target product can be obtained by stirring the reaction under normal pressure, and the yield reaches more than 75%, which greatly simplifies the process engineering, reduces energy consumption, and has the advantages of high yield. In addition, less waste solution is produced during the reaction, and no other polluting gas and liquid are discharged. Therefore, the method reduces the discharge of waste solution, has the advantages of protecting the environment and ensuring the health of operators. In addition, a series of triaryl acrylonitrile can be prepared, and the method has strong substrate universality, which provides a good guarantee for the development of organic compounds related to triaryl acrylonitrile.

[0058] The above is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments. All technical solutions under the concept of the present invention belong to the protection scope of the present invention. It should be pointed out that for ordinary technicians in this technical field, some improvements and modifications without departing from the principle of the present invention should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing triaryl acrylonitrile, characterized in that: Under the action of inert gas and palladium catalyst, iodobenzene substances, benzyl cyanide substances, phosphorus ligands, oxidants, and bases are stirred and mixed in an organic solvent, and after being mixed evenly, heated to react, thereby obtaining triaryl acrylonitrile; The structural formula of the iodobenzene substance is , wherein R1 is any one of methyl, methoxy and nitro; The structural formula of the benzyl cyanide substance is , wherein R2 is any one of methyl, methoxy, and nitro; The reaction formula is ； The palladium catalyst is any one of bisacetonitrile palladium chloride, palladium trifluoroacetate, bis(triphenylphosphine)palladium chloride, tetrakis(triphenylphosphine)palladium, palladium acetate, palladium bromide and tris(dibenzylideneacetone)dipalladium; The phosphorus ligand is any one of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, tricyclohexylphosphine, 4,5-bisdiphenylphosphine-9,9'-dimethylxanthene, 2-(dicyclohexylphosphine)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl and 2-(di-tert-butylphosphine)biphenyl; The oxidant is manganese dioxide; The alkali is any one of sodium hydroxide, potassium hydroxide and potassium carbonate.

2. A method for synthesizing triaryl acrylonitrile according to claim 1, characterized in that: The inert gas is any one of nitrogen, argon and helium.

3. The method for synthesizing triaryl acrylonitrile according to claim 1, characterized in that: The organic solvent is any one of n-hexane, methanol, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, isopropanol and 1,2-dichloroethane.

4. A method for synthesizing triaryl acrylonitrile according to claim 1, characterized in that: During the reaction, the molar ratio of iodobenzene, benzyl cyanide, palladium catalyst, phosphorus ligand, oxidant and base is 1.0: 2.0-4.0: 0.05-0.15: 0.1-0.2: 0.15-0.4: 2-3.

5. The method for synthesizing triaryl acrylonitrile according to claim 1, characterized in that: The heating reaction specifically refers to reacting at a temperature of 110-180° C. for 24-50 hours.

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