CN115490613B - A kind of preparation method of aromatic nitrile compound - Google Patents

Abstract

The present invention discloses a preparation method for aromatic crickets. The method includes: carboxylic acid compounds are raw materials, first add cyanide, special amnate anhydride, metal catalysts, ligands, solvents, react to 8‑16h at 120 ° C to 180 ° C, the reaction solution is cooled to room temperature, and the aromatherapy compounds shown (Ⅱ) are used. The stable structural and easy to store is an additive. As an additive, it efficiently promotes the carboxylic acid to generate an anhydride intermediate. At the same time, it uses low -priced and environmentally friendly cyanide zinc as the source of cyanide. The use of other highly toxic and unstable dangerous reagents is avoided, and the corresponding aromatic nitrile compounds can be obtained in good yields. The operation process is simple, and the post-treatment only needs to be separated and purified by column chromatography to obtain the target product.

Description

A kind of preparation method of aromatic nitrile compound

(1) Technical field

The invention relates to a preparation method of aromatic nitrile compounds, in particular to a preparation method using zinc cyanide as a cyanide source, pivalic anhydride as an additive, and a carboxylic acid compound as a substrate to undergo a decarbonylation cyanation reaction under metal catalysis to generate a nitrile compound.

(2) Background technology

Aromatic nitriles are ubiquitous biologically active organic compounds, so they are often used as pharmaceuticals, agrochemicals, and biologically active natural products. The traditional methods for the synthesis of aromatic nitriles include Sandmeyer and Rosenmundvon Braun, but their disadvantages are that they need to use toxic reagents or be realized under high temperature conditions, and their substrate range is narrow. So far, how to develop a novel and effective method to construct aromatic nitriles is still an active topic in organic chemical synthesis. In recent years, the use of transition metal-catalyzed nucleophilic cyanation of aryl halides or pseudohalides with various CN sources to prepare aryl nitrile compounds is a class of efficient methods. In contrast, carboxylic acid functional groups are ubiquitous, stable and readily available, and widely used in organic synthesis. Scientists have developed many strategies to use carboxylic acid derivatives as reactive groups to form CC bonds via decarboxylation or decarbonylation. At the same time, metal-catalyzed decarbonylation reactions are gradually being used to synthesize aromatic nitriles. For example, Szostak's research group has successfully developed palladium-catalyzed decarbonylation of amides to synthesize various aryl nitriles [Org. A _series of nitrile compounds were synthesized under neutral conditions in the decarbonylation reaction [Org. Lett., 2019, 21, 17, 6779.]. However, these methods have some disadvantages, such as the need for pre-synthesis of carboxylic acid derivatives or the use of unstable and odorous starting acid chlorides.

(3) Contents of the invention

Aiming at the defects existing in the prior art, the present invention provides a new method for synthesizing aromatic nitrile compounds with high efficiency, environmental protection, economy and speed. The present invention adopts cheap and easy-to-obtain zinc cyanide as a cyanide source, uses stable and easy-to-storage pivalic anhydride as an additive, and uses common carboxylic acid compounds as substrates to synthesize aromatic nitrile compounds by decarbonylation cyanation reaction under the catalysis of a metal catalyst.

The technical scheme adopted in the present invention is:

The present invention provides a kind of preparation method of aromatic nitrile compound shown in formula (II), described method comprises:

Using the carboxylic acid compound represented by formula (I) as raw material, adding zinc cyanide, pivalic anhydride, metal catalyst, ligand and organic solvent, reacting at 120°C to 180°C for 8-16h under nitrogen atmosphere, and post-processing the reaction solution to obtain the aromatic nitrile compound represented by formula (II);

The metal catalyst is one of the following: palladium chloride, palladium trifluoroacetate, palladium acetylacetonate, palladium acetate or bisdibenzylideneacetone palladium;

The ligand is one of the following: bis(diphenylphosphine)methane (Dppm), 1,4-bis(diphenylphosphine)butane (Dppb), 1,5-bis(diphenylphosphine)pentane (Dpppe), 1,1'-bis(diphenylphosphine)ferrocene (Dppf), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos), bis(2-diphenylphosphine)phenyl ether (DPEPhos) or Triphenylphosphine (PPh ₃ );

The organic solvent is one of the following: toluene, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, ethyl acetate or N-methylpyrrolidone;

R in formula (I) is an aromatic group, C1-C6 linear or branched chain alkyl, and R in formula (II) is the same as R in formula (I).

Preferably, R in the formula (I) is 4-aphenyl, 4-phenyl, 4-methoxy, 4-methylformate, 4-acetyl.

Further, the ratio of the zinc cyanide to the carboxylic acid compound represented by formula (I) is 1-5:1, preferably 1-3:1, more preferably 1.5:1. The volumetric usage of the organic solvent is 1-10 mL/mmol, preferably 5 mL/mmol, based on the amount of the carboxylic acid compound represented by the formula (I). The ratio of the pivalic anhydride to the carboxylic acid compound represented by formula (I) is 1-5:1, preferably 1.5:1. The ratio of the amount of the metal catalyst to the carboxylic acid compound represented by formula (I) is 0.01-0.3:1, preferably 0.05:1. The amount ratio of the carboxylic acid compound represented by the ligand formula (I) is 0.01-0.6:1, preferably 0.05:1.

Further, the reaction temperature is preferably 150-170° C., and the reaction time is 12 hours.

Further, the post-treatment method of the reaction liquid is: after the reaction is completed, the reaction liquid is cooled to room temperature, and the₂Cl₂Dilute, filter, and concentrate the filtrate to dryness to obtain the crude product; dissolve the crude product in dichloromethane, add silica gel powder and mix evenly, concentrate to dryness, apply dry method to the silica gel chromatography column, use petroleum ether:ethyl acetate at a volume ratio of 10 to 30:1 as the eluent for silica gel column chromatography, and use petroleum ether:ethyl acetate at a volume ratio of 10 to 30:1 as the developer for thin-layer chromatography monitoring, collect the eluent with Rf=0.3 to 0.7, and concentrate the eluent to dry to obtain the aromatic nitrile compound represented by formula (II).

Preferably, the particle size of the silica gel powder is 300-400 mesh, the diameter of the silica gel chromatography column is 3 cm, the height is 30 cm, and the column packing height is 16 cm.

Preferably, the volumetric dosage of dichloromethane is 0.1-1.0mL/mg in terms of crude product mass, preferably 0.15-0.25mL/mg; the mass ratio of crude product to silica gel powder is 1:50-80.

Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

1. The present invention uses pivalic anhydride, which has a stable structure and is easy to store, as an additive to efficiently promote the production of anhydride intermediates from carboxylic acids.

2. The present invention uses zinc cyanide, which is cheap, easy to get, and environmentally friendly, as the cyanide source.

3. Zinc cyanide and pivalic anhydride avoid the use of other highly toxic and unstable dangerous reagents.

4. The substrate has wide applicability, and the yield of aromatic nitrile compounds is 40-97%.

5. Solve the cumbersome problem of needing to synthesize and purify carboxylic acid derivatives as raw materials in advance, and optimize the use of odorous and unstable reagents.

6. The operation process is simple, and the post-treatment only needs to be separated and purified by column chromatography to obtain the target product.

(4) Description of drawings

Fig. 1 is the proton nuclear magnetic resonance spectrum (A), the carbon spectrum (B) figure, the mass spectrum (C) figure of the compound prepared in Example 1.

Fig. 2 is the proton nuclear magnetic resonance spectrum (A), the carbon spectrum (B) figure, the mass spectrum (C) figure of the compound prepared in Example 2.

Fig. 3 is the proton nuclear magnetic resonance spectrum (A), the carbon spectrum (B) figure, the mass spectrum (C) figure of the compound prepared in Example 3.

Fig. 4 is the proton nuclear magnetic resonance spectrum (A), the carbon spectrum (B) figure, the mass spectrum (C) figure of the compound prepared in Example 4.

Fig. 5 is the proton nuclear magnetic resonance spectrum (A), the carbon spectrum (B) figure, the mass spectrum (C) figure of the compound prepared in Example 5.

(5) Specific implementation methods

The present invention will be further described below in conjunction with specific examples, but the protection scope of the present invention is not limited thereto: the room temperature in the present invention refers to 25-30°C.

Example 1: Naphthalene-2-carbonitrile

In a 25mL Shrek tube, add 0.0344g (0.2mmol) of 2-naphthoic acid represented by formula (I-1), 0.0235g (0.2mmol) zinc cyanide, 0.0559g (0.3mmol) pivalic anhydride, 0.0022g (0.01mmol) palladium acetate, 0.0174g (0.03mmol) 4,5-bis(diphenylphosphine)- 9,9-Dimethylxanthene (Xantphos), 1 mL of 1,4-dioxane solvent; under nitrogen replacement, the reaction mixture was placed in a preheated oil bath at 160°C, and reacted at 160°C for 12h. After the reaction, the reaction mixture was cooled to room temperature, diluted with CH ₂ Cl ₂ (10 mL), filtered, and the filtrate was concentrated to dryness to obtain 52.5 mg of crude product.

After dissolving 52.5 mg of the crude product in 10 mL of dichloromethane, add 3 g of silica gel powder (300-400 mesh in particle size) and mix evenly, concentrate to dryness, and dry-pack a silica gel chromatography column (30 cm in height, 3 cm in diameter, and 16 cm in height), perform silica gel column chromatography with petroleum ether:ethyl acetate at a volume ratio of 20:1 as the eluent, and perform thin-layer chromatography monitoring with petroleum ether:ethyl acetate at a volume ratio of 20:1 as a developer. The f=0.45 eluate was concentrated to dryness to obtain 27.6 mg of naphthalene-2-carbonitrile represented by formula (II-1), with a yield of 90%. See A in Figure 1 for the proton NMR spectrum, B in Figure 1 for the carbon NMR spectrum, and C in Figure 1 for the mass spectrum.

Proton NMR spectrum: (400MHz, CDCl ₃ ) δ8.19(s, 1H), 7.88(t, J=7.1Hz, 3H), 7.68–7.53(m, 3H).

Carbon NMR spectrum: (101MHz, CDCl ₃ ) δ134.65, 134.17, 132.24, 129.23, 129.09, 128.44, 128.09, 127.70, 126.34, 119.31, 109.35.

Mass Spectrum: HRMS(EI) calcd for C ₁₁ H ₇ N: 153.0578; Found: 153.0583.

Comparative Example 1: Naphthalene-2-carbonitrile

In a 25mL Shrek tube, sequentially add 0.0344g (0.2mmol) of 2-naphthoic acid represented by formula (I-1), 0.0235g (0.2mmol) of zinc cyanide, 0.0022g (0.01mmol) of palladium acetate, 0.0174g (0.03mmol) of 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos), 1mL1 , 4-dioxane solvent; in the state of nitrogen replacement, the reaction mixture was placed in a preheated oil bath at 160°C, and reacted at 160°C for 12h. After the reaction, the reaction solution was detected, and no naphthalene-2-carbonitrile was found after the detection, indicating that it is necessary and useful to add pivalic anhydride in this reaction.

Comparative Example 2: Naphthalene-2-carbonitrile

In Example 1, 0.0198g (0.2mmol) trimethylnitrile silane was used instead of zinc cyanide, other conditions and operations were the same as in Example 1, and the reaction solution was detected, and no product was produced.

Comparative Example 3: Naphthalene-2-carbonitrile

In Example 1, 0.0737g (0.2mmol) potassium ferrocyanide was used instead of zinc cyanide. Other conditions and operations were the same as in Example 1. The reaction solution was detected, and no product was produced.

Example 2: [1,1'-biphenyl]-4-carbonitrile

In a 25mL Shrek tube, sequentially add 0.0396g (0.2mmol) of biphenyl-4-carboxylic acid shown in formula (I-2), 0.0235g (0.2mmol) zinc cyanide, 0.0559g (0.3mmol) pivalic anhydride, 0.0022g (0.01mmol) palladium acetate, 0.0174g (0.03mmol) 4,5-bis(diphenylphosphine) )-9,9-dimethylxanthene (Xantphos), 1mL of 1,4-dioxane solvent; under the state of nitrogen replacement, the reaction mixture was placed in a preheated oil bath at 160°C, and reacted at 160°C for 12h. After the reaction, the reaction mixture was cooled to room temperature, diluted with CH ₂ Cl ₂ (10 mL), filtered, and the filtrate was concentrated to dryness to obtain 65.3 mg of crude product.

After dissolving 65.3 mg of the crude product in 10 mL of dichloromethane, add 5 g of silica gel powder (300-400 mesh) and mix evenly, concentrate to dryness, and dry-load the sample to a silica gel chromatography column (column diameter 3 cm, height 30 cm, column height 16 cm). Carry out silica gel column chromatography with a volume ratio of 20:1 petroleum ether:ethyl acetate as the eluent, and use a volume ratio of 20:1 petroleum ether:ethyl acetate as a developer for TLC monitoring. The eluent with Rf=0.63 obtained 33.0 mg of [1,1'-biphenyl]-4-carbonitrile represented by formula (II-2), with a yield of 92%. See A in Figure 2 for the proton NMR spectrum, B in Figure 2 for the carbon NMR spectrum, and C in Figure 2 for the mass spectrum.

Proton NMR spectrum: (400MHz, CDCl ₃ ) δ7.71(q, J=8.5Hz, 4H), 7.62–7.57(m, 2H), 7.49(t, J=7.3Hz, 2H), 7.46–7.40(m, 1H).

Carbon NMR spectrum: (101MHz, CDCl ₃ ) δ145.76, 139.25, 132.70, 129.22, 128.77, 127.83, 127.33, 119.08, 110.97.

Mass Spectrum: HRMS(EI) calcd for C ₁₃ H ₉ N: 179.0735; Found: 179.0738.

Example 3: Methyl 4-cyanobenzoate

In a 25mL Shrek tube, sequentially add 0.0360g (0.2mmol) of monomethyl terephthalate shown in formula (I-3), 0.0235g (0.2mmol) of zinc cyanide, 0.0559g (0.3mmol) of pivalic anhydride, 0.0022g (0.01mmol) of palladium acetate, 0.0174g (0.03mmol) of 4,5-bis(diphenyl Phosphine)-9,9-dimethylxanthene (Xantphos), 1mL of 1,4-dioxane solvent; under nitrogen replacement, the reaction mixture was placed in a preheated oil bath at 160°C, and reacted at 160°C for 12h. After the reaction, the reaction mixture was cooled to room temperature, diluted with CH ₂ Cl ₂ (10 mL), filtered, and the filtrate was concentrated to dryness to obtain 58.3 mg of crude product.

After dissolving 58.3 mg of the crude product in 10 mL of dichloromethane, add 3 g of silica gel powder (300-400 mesh) and mix evenly, concentrate to dryness, and dry-load the sample to a silica gel chromatography column (column diameter 3 cm, height 30 cm, column height 16 cm). Carry out silica gel column chromatography with petroleum ether:ethyl acetate at a volume ratio of 10:1 as eluent, and perform TLC monitoring with petroleum ether:ethyl acetate at a volume ratio of 10:1 as a developing solvent. The eluent with Rf=0.56 gave 25.8 mg of methyl 4-cyanobenzoate represented by formula (II-3), with a yield of 80%. See A in Figure 3 for the proton NMR spectrum, B in Figure 3 for the carbon NMR spectrum, and C in Figure 3 for the mass spectrum.

Proton NMR spectrum: (400MHz, CDCl ₃ ) δ8.18–8.02(m,2H),7.78–7.61(m,2H),3.92(s,3H).

Carbon NMR spectrum: (101MHz, CDCl ₃ ) δ165.42, 133.91, 132.24, 130.09, 117.97, 116.36, 52.74.

Mass Spectrum: HRMS(EI) calcd for C ₉ H ₇ NO ₂ : 161.0477; Found: 161.0485.

Example 4: 4-methoxybenzonitrile

In a 25mL Shrek tube, add 0.0304g (0.2mmol) of 4-methoxybenzoic acid shown in formula (I-4), 0.0235g (0.2mmol) zinc cyanide, 0.0559g (0.3mmol) pivalic anhydride, 0.0022g (0.01mmol) palladium acetate, 0.0174g (0.03mmol) 4,5-bis(diphenylphosphine) )-9,9-dimethylxanthene (Xantphos), 1mL of 1,4-dioxane solvent; under the state of nitrogen replacement, the reaction mixture was placed in a preheated oil bath at 160°C, and reacted at 160°C for 12h. After the reaction, the reaction mixture was cooled to room temperature, diluted with CH ₂ Cl ₂ (10 mL), filtered, and the filtrate was concentrated to dryness to obtain 48.9 mg of crude product.

After dissolving 48.9 mg of the crude product in 10 mL of dichloromethane, add 3 g of silica gel powder (300-400 mesh) and mix evenly, concentrate to dryness, and dry-load the sample to a silica gel chromatography column (column diameter 3 cm, height 30 cm, column height 16 cm). Carry out silica gel column chromatography with petroleum ether:ethyl acetate at a volume ratio of 30:1 as the eluent, and perform thin-layer chromatography monitoring with petroleum ether:ethyl acetate at a volume ratio of 30:1 as a developer. The eluent with Rf=0.65 gave 24.0 mg of 4-methoxybenzonitrile represented by formula (II-4), with a yield of 90%. See A in Figure 4 for the proton NMR spectrum, B in Figure 4 for the carbon NMR spectrum, and C in Figure 4 for the mass spectrum.

Proton NMR spectrum: (400MHz, CDCl ₃ ) δ7.62–7.55(m,2H),6.98–6.91(m,2H),3.85(s,3H).

Carbon NMR spectrum: (101MHz, CDCl ₃ ) δ162.86, 134.01, 119.27, 114.77, 103.94, 55.58.

Mass Spectrum: HRMS(EI) calcd for C ₈ H ₇ NO:133.0528; Found: 133.0530.

Example 5: 4-acetylbenzonitrile

In a 25mL Shrek tube, add 0.0328g (0.2mmol) of 4-acetylbenzoic acid represented by formula (Ⅰ-5), 0.0235g (0.2mmol) zinc cyanide, 0.0559g (0.3mmol) pivalic anhydride, 0.0022g (0.01mmol) palladium acetate, 0.0174g (0.03mmol) 4,5-bis(diphenyl Phosphine)-9,9-dimethylxanthene (Xantphos), 1mL of 1,4-dioxane solvent; under nitrogen replacement, the reaction mixture was placed in a preheated oil bath at 160°C, and reacted at 160°C for 12h. After the reaction, the reaction mixture was cooled to room temperature, diluted with CH ₂ Cl ₂ (10 mL), filtered, and the filtrate was concentrated to dryness to obtain 38.6 mg of crude product.

After dissolving 38.6 mg of the crude product in 10 mL of dichloromethane, add 2.5 g of silica gel powder (300-400 mesh) and mix well, concentrate to dryness, and apply the dry method to a silica gel chromatography column (column diameter 3 cm, height 30 cm, column height 16 cm), perform silica gel column chromatography with volume ratio 10:1 petroleum ether:ethyl acetate as eluent, and use volume ratio 10:1 petroleum ether:ethyl acetate as developing solvent for thin layer chromatography Monitor and collect the eluate with Rf=0.53 to obtain 17.4 mg of 4-acetylbenzonitrile represented by formula (II-5), with a yield of 60%. See A in Figure 5 for the proton NMR spectrum, B in Figure 5 for the carbon NMR spectrum, and C in Figure 5 for the mass spectrum.

Proton NMR spectrum: (400MHz, CDCl ₃ ) δ8.08–7.98(m,2H), 7.79–7.70(m,2H), 2.62(s,3H).

Carbon NMR spectrum: (101MHz, CDCl ₃ ) δ196.63, 139.91, 132.54, 128.73, 117.97, 116.36, 26.81.

Mass Spectrum: HRMS(EI) calcd for C ₉ H ₇ NO: 145.0528; Found: 145.0534.

Claims (6)

1. a preparation method of aromatic nitrile compound, is characterized in that, described method comprises: Using the carboxylic acid compound represented by formula (I) as raw material, adding zinc cyanide, pivalic anhydride, metal catalyst, ligand and organic solvent, reacting at 120°C to 180°C for 8-16h under nitrogen atmosphere, and post-processing the reaction solution to obtain the aromatic nitrile compound represented by formula (II); The metal catalyst is one of the following: palladium chloride, palladium trifluoroacetate, palladium acetylacetonate, palladium acetate or bisdibenzylideneacetone palladium; The ligand is one of the following: bis(diphenylphosphine)methane, 1,4-bis(diphenylphosphine)butane, 1,5-bis(diphenylphosphine)pentane, 1,1'-bis(diphenylphosphine)ferrocene, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, bis(2-diphenylphosphine)phenyl ether or triphenylphosphine; The organic solvent is one of the following: toluene, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, ethyl acetate or N-methylpyrrolidone; R in formula (I) is 4-aphenyl, 4-phenyl, 4-methoxy, 4-methyl formate, 4-acetyl, and R in formula (II) is the same as R in formula (I). 2. the preparation method of aromatic nitrile compound as claimed in claim 1, it is characterized in that, the ratio of the amount of substance of carboxylic acid compounds shown in the zinc cyanide and formula (I) is 1～5:1; The volume consumption of described organic solvent is counted as 1～10mL/mmol with the amount of carboxylic acid compounds shown in formula (I); The ratio of the amount of substance of carboxylic acid compounds shown in the described pivalic anhydride and formula (I) is 1～5:1; The amount ratio is 0.01-0.3:1; the amount ratio of the carboxylic acid compound represented by the ligand formula (I) is 0.01-0.6:1. 3. The preparation method of aromatic nitrile compounds as claimed in claim 1, characterized in that, the reaction temperature is 150-170°C, and the reaction time is 12h. 4. the preparation method of aromatic nitrile compound as claimed in claim 1, is characterized in that, described reaction solution aftertreatment method is: after reaction finishes, reaction solution is cooled to room temperature, with 10～30 times of volume CH₂Cl₂Dilute, filter, and concentrate the filtrate to dryness to obtain the crude product; dissolve the crude product in dichloromethane, add silica gel powder and mix evenly, concentrate to dryness, apply dry method to the silica gel chromatography column, use petroleum ether:ethyl acetate at a volume ratio of 10 to 30:1 as the eluent for silica gel column chromatography, and use petroleum ether:ethyl acetate at a volume ratio of 10 to 30:1 as the developer for thin-layer chromatography monitoring, collect the eluent with Rf=0.3 to 0.7, and concentrate the eluent to dry to obtain the aromatic nitrile compound represented by formula (II). 5. the preparation method of aromatic nitrile compound as claimed in claim 4 is characterized in that, described silica gel powder particle diameter 300-400 order, the diameter of silica gel chromatography column is 3cm, high 30cm, packing height 16cm. 6. the preparation method of aromatic nitrile compound as claimed in claim 4, is characterized in that, described dichloromethane volume consumption is 0.1-1.0mL/mg by crude product quality; Described crude product and silica gel powder mass ratio are 1:50-80.