CN115074760B - Electrochemical synthesis method of 5-aminopyrazole-4-thiocyanate compounds - Google Patents

Abstract

The invention discloses an electrochemical synthesis method of 5-aminopyrazole-4-thiocyanate compounds, relates to the technical field of organic electrochemical synthesis, and includes the following steps: (1) electrocatalytic reaction: converting thiocyanate , 5-amino pyrazole compounds, acids, and solvents were added to the reaction tank respectively, and catalytic electrodes were installed, and electricity was applied to stir the reaction; (2) Separation and purification: The solution after the electrocatalytic reaction was completed was separated and purified to obtain 5-amino pyrazole compounds. Pyrazole‑4‑thiocyanates. The present invention uses thiocyanate and 5-aminopyrazole compounds as reaction raw materials, and synthesizes 5-aminopyrazole-4-thiocyanate compounds in one pot under electrochemical conditions. This method does not require metal and chemicals. The use of oxidants has high reaction atom economy and meets the requirements for the development of green chemistry.

Description

Electrochemical synthesis method of 5-aminopyrazole-4-thiocyanate compounds

Technical areas:

The invention relates to the technical field of organic electrochemical synthesis, and specifically relates to an electrochemical synthesis method of 5-aminopyrazole-4-thiocyanate compounds.

Background technique:

Pyrazole is a five-membered heterocyclic compound containing two connected nitrogen atoms, and its derivatives are widely found in synthetic chemicals. Because of its high efficiency and broad-spectrum biological activity and wide application in the fields of medicine and agricultural chemicals, it has been receiving widespread attention from workers in organic chemistry, medicinal chemistry, biology and other related fields for many years, especially those with antifungal activity. N-aryl-5-aminopyrazole-4-thiocyanate compound is effective against Trichophyton floccosum and Trichophyton rubrum. The study found that the inhibitory effect of this molecule on these two types of fungi is no less than the clinical standard drug ketoconazole. Therefore, the study of its synthesis methods has always been the focus of organic chemists. However, due to the presence of amino groups in the reaction substrate, it is difficult to be compatible in the oxidation system. Currently, there are few studies on the synthesis of 5-aminopyrazole-4-thiocyanate compounds.

In 2020, Choudhury's research group reported the hydrogen peroxide-promoted C(sp2)-H bond thiocyanation reaction of N-aryl-5-aminopyrazole compounds, and synthesized a series of N-aryl-5-amino pyrazole compounds. Compounds of pyrazole-4-thiocyanate (D. Ali, A. K. Panday, L. H. Choudhury. J. Org. Chem. 2020, 85, 13610). Although this method can achieve its synthesis well, it requires a large amount of hydrogen peroxide (8 equivalents). The use of a large amount of chemical oxidants will lead to complex reaction systems and low atom economy, which will cause a large amount of waste liquid discharge during industrial production.

Contents of the invention:

The technical problem to be solved by the present invention is to provide an electrochemical synthesis method of 5-aminopyrazole-4-thiocyanate compounds, using a green organic electrochemical synthesis method in a reaction environment without adding metals and chemical oxidants. Under this method, 5-aminopyrazole-4-thiocyanate compounds are prepared to overcome the shortcomings of the existing technology.

The object of the present invention is to provide an electrochemical synthesis method of 5-aminopyrazole-4-thiocyanate compounds, which includes the following steps:

(1) Electrocatalytic reaction: Add thiocyanate, 5-aminopyrazole compounds, acid, and solvent to the reaction tank respectively, install a catalytic electrode, and turn on electricity to stir the reaction;

(2) Separation and purification: The solution after the electrocatalytic reaction is completed is separated and purified to obtain 5-aminopyrazole-4-thiocyanate compounds.

The 5-aminopyrazole-4-thiocyanate compound has the structure shown below:

Among them, R ¹ is hydrogen, C ₁ to C ₅ alkyl group, and aryl group; R ² is an aryl group and ester group.

The beneficial effects of the present invention are: the present invention provides an electrochemical synthesis method of 5-aminopyrazole-4-thiocyanate compounds, using thiocyanate and 5-aminopyrazole compounds as reaction raw materials, 5-Aminopyrazole-4-thiocyanate compounds were synthesized in one pot under electrochemical conditions. This method does not require the use of metals and chemical oxidants, has high reaction atom economy, and meets the requirements for the development of green chemistry.

Picture description:

Figure 1 is ¹ H NMR of the product obtained in Example 1 of the present invention;

Figure 2 is ¹³ C NMR of the product obtained in Example 1 of the present invention;

Figure 3 is ¹ H NMR of the product obtained in Example 2 of the present invention;

Figure 4 is ¹³ C NMR of the product obtained in Example 2 of the present invention;

Figure 5 is ¹ H NMR of the product obtained in Example 3 of the present invention;

Figure 6 is ¹³ C NMR of the product obtained in Example 3 of the present invention;

Figure 7 is ¹ H NMR of the product obtained in Example 4 of the present invention;

Figure 8 is ¹³ C NMR of the product obtained in Example 4 of the present invention;

Figure 9 is ¹ H NMR of the product obtained in Example 5 of the present invention;

Figure 10 is ¹³ C NMR of the product obtained in Example 5 of the present invention;

Figure 11 is ¹ H NMR of the product obtained in Example 6 of the present invention;

Figure 12 is ¹³ C NMR of the product obtained in Example 6 of the present invention.

Detailed ways:

In order to make it easy to understand the technical means, creative features, objectives and effects of the present invention, the present invention will be further elaborated below with reference to specific embodiments and illustrations.

The invention provides an electrochemical synthesis method of 5-aminopyrazole-4-thiocyanate compounds, which includes the following steps:

(1) Electrocatalytic reaction: Add thiocyanate, 5-aminopyrazole compounds, acid, and solvent to the reaction tank respectively, install a catalytic electrode, and turn on electricity to stir the reaction;

(2) Separation and purification: The solution after the electrocatalytic reaction is completed is separated and purified to obtain 5-aminopyrazole-4-thiocyanate compounds.

The 5-aminopyrazole-4-thiocyanate compound has the structure shown below:

Among them, R ¹ is hydrogen, C ₁ to C ₅ alkyl group, and aryl group; R ² is an aryl group and ester group.

Preferably, the thiocyanate is one of potassium thiocyanate, ammonium thiocyanate, and sodium thiocyanate.

Preferably, the 5-aminopyrazole compound has the structure shown below:

Among them, R ¹ is hydrogen, C ₁ to C ₅ alkyl group, and aryl group; R ² is an aryl group and ester group.

Preferably, the material ratio of the 5-aminopyrazole compound to the thiocyanate is 1:1 to 1:4.

Preferably, the initial concentration of the 5-aminopyrazole compound is 0.05-0.2 mol/L.

Preferably, the acid is one of acetic acid (acetic acid), benzoic acid, hydrochloric acid, sulfuric acid, and diphenylphosphoric acid, and the amount of the substance is 30 to 120% of the amount of the 5-aminopyrazole compound.

Preferably, the temperature of the stirring reaction is 0 to 80°C.

Preferably, the solvent is dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, N-methylpyrrolidone, N,N-dimethylacetamide, acetonitrile, water, 1,2 - One or more dichloroethanes.

Preferably, the electrode is a conventional commercially available electrode material, such as platinum electrode, carbon electrode, nickel electrode, copper electrode, etc.

Preferably, the separation and purification method is one of column chromatography, liquid chromatography, distillation, and recrystallization. Further preferably, the separation and purification method is column chromatography. The solution after the reaction was completed was spun to dryness under reduced pressure, and the residue was separated using a silica gel column chromatography column.

The eluent of the column chromatography is petroleum ether/ethyl acetate. This does not mean that other eluent systems cannot be used. Any reagent that meets the purpose of elution can be used.

The chemical reaction formula of 5-aminopyrazole-4-thiocyanate compounds is as follows:

For the first time, the present invention realizes the reaction between 5-aminopyrazole compounds and thiocyanate under electrochemical conditions to obtain 5-aminopyrazole-4-thiocyanate compounds with high selectivity. This method is a green and efficient method for synthesizing 5-aminopyrazole-4-thiocyanate compounds.

The 5-aminopyrazole compounds and thiocyanates used in the examples were all analytically pure reagents purchased directly from Anaiji Chemical, Jiuding Chemical, Aladdin and Adamas. They were not otherwise used before use. For treatment, the solvent or eluent used was purchased from Sinopharm.

Example 1

Put 3-methyl-1-phenyl-1H-pyrazole-5-amine (0.3mmoL, 52.0mg), potassium thiocyanate (0.6mmol, 58.3mg), acetic acid ( 0.3mmol, 18.2mg), acetonitrile (2.5mL) and water (0.5mL). The platinum electrode serves as both anode and cathode. The reaction is stirred by electricity (I=5mA) at room temperature and followed by TLC for detection. After the reaction is completed, the residue obtained is spin-dried and passed through a chromatographic column using an ethyl acetate/petroleum ether system as the eluent to obtain the product 3-methyl-1-phenyl-4-thiocyanate-1H-pyrazole-5. - Amine compound, yield 94%.

The obtained product 3-methyl-1-phenyl-4-thiocyanato-1H-pyrazole-5-amine was structurally analyzed by a nuclear magnetic resonance spectrometer. The results are shown in Figures 1 to 2. Figure 1 is a ¹ H nuclear magnetic resonance ( ¹ H-NMR) spectrum of the 3-methyl-1-phenyl-4-thiocyanato-1H-pyrazole-5-amine product prepared in Example 1 of the present invention; Figure 2 is the ¹³ C nuclear magnetic resonance ( ¹³ C-NMR) spectrum of the 3-methyl-1-phenyl-4-thiocyano-1H-pyrazole-5-amine product prepared in Example 1 of the present invention. ¹ H NMR (DMSO-d ₆ , 400MHz, ppm): δ = 7.53-7.49 (m, 4H), 7.41-7.36 (m, 1H), 6.34 (br, 2H), 2.19 (s, 3H); ¹³ C NMR (DMSO-d ₆ , 100MHz, ppm): δ = 150.6, 150.3, 138.3, 129.4, 127.2, 123.4, 112.4, 75.1, 12.0.

Example 2

Put 3-tert-butyl-1-phenyl-1H-pyrazole-5-amine (0.3mmoL, 64.6mg), potassium thiocyanate (0.6mmol, 58.3mg), and acetic acid into a 10mL non-separated electrolytic tank. (0.3mmol, 18.2mg), acetonitrile (2.5mL) and water (0.5mL). The platinum electrode serves as both anode and cathode. The reaction is stirred by electricity (I=5mA) at room temperature and followed by TLC for detection. After the reaction is completed, the residue obtained is spin-dried and passed through a chromatographic column using an ethyl acetate/petroleum ether system as the eluent to obtain the product 3-tert-butyl-1-phenyl-4-thiocyanate-1H-pyrazole- 5-amine compound, yield 91%.

The obtained product 3-tert-butyl-1-phenyl-4-thiocyanato-1H-pyrazole-5-amine was structurally analyzed by a nuclear magnetic resonance spectrometer. The results are shown in Figures 3 to 4. Figure 3 is a ¹ H nuclear magnetic resonance ( ¹ H-NMR) spectrum of the 3-tert-butyl-1-phenyl-4-thiocyanato-1H-pyrazole-5-amine product prepared in Example 2 of the present invention; Figure 4 is a ¹³ C nuclear magnetic resonance ( ¹³ C-NMR) spectrum of the 3-tert-butyl-1-phenyl-4-thiocyanato-1H-pyrazole-5-amine product prepared in Example 2 of the present invention. ¹ H NMR (CDCl ₃ , 400MHz, ppm): δ = 7.53-7.47 (m, 4H), 7.40-7.36 (m, 1H), 4.44 (br, 2H), 1.48 (s, 9H); ¹³ C NMR ( CDCl ₃ , 100MHz, ppm): δ = 161.0, 149.5, 137.9, 129.7, 128.0, 123.8, 111.5, 74.8, 33.4, 29.2.

Example 3

Put 1,3-diphenyl-1H-pyrazole-5-amine (0.3mmoL, 70.5mg), potassium thiocyanate (0.6mmol, 58.3mg), acetic acid (0.3mmol) into a 10mL non-separated electrolytic tank. , 18.2 mg), acetonitrile (2.5 mL) and water (0.5 mL). The platinum electrode serves as both anode and cathode. The reaction is stirred by electricity (I=5mA) at room temperature and followed by TLC for detection. After the reaction is completed, the residue obtained is spin-dried and passed through a chromatographic column using an ethyl acetate/petroleum ether system as the eluent to obtain the product 1,3-diphenyl-4-thiocyanato-1H-pyrazole-5-amine. compound with a yield of 80%.

The obtained product 1,3-diphenyl-4-thiocyanato-1H-pyrazole-5-amine was structurally analyzed by a nuclear magnetic resonance spectrometer. The results are shown in Figures 5 to 6. Figure 5 shows the preparation of Example 3 of the present invention. The ¹ H nuclear magnetic resonance ( ¹ H-NMR) spectrum of the 1,3-diphenyl-4-thiocyano-1H-pyrazole-5-amine product; Figure 6 is 1 prepared in Example 3 of the present invention, ¹³ C nuclear magnetic resonance ( ¹³ C-NMR) spectrum of the 3-diphenyl-4-thiocyanato-1H-pyrazole-5-amine product. ¹ H NMR (CDCl ₃ , 400MHz, ppm): δ = 7.92-7.89 (m, 2H), 7.59-7.42 (m, 8H), 4.58 (br, 2H); ¹³ C NMR (CDCl ₃ , 100MHz, ppm) :δ=152.7,149.4,137.6,131.3,129.8,128.9,128.5,128.5,127.9,124.0,111.2,76.0.

Example 4

Put 1-phenyl-1H-pyrazole-5-amine (0.3mmoL, 47.7mg), potassium thiocyanate (0.6mmol, 58.3mg), and acetic acid (0.3mmol, 18.2mg) into a 10mL non-separated electrolytic tank. ), acetonitrile (2.5 mL) and water (0.5 mL). The platinum electrode serves as both anode and cathode. The reaction is stirred by electricity (I=5mA) at room temperature and followed by TLC for detection. After the reaction is completed, the residue obtained is spin-dried and passed through a chromatographic column using an ethyl acetate/petroleum ether system as the eluent to obtain the product 1-phenyl-4-thiocyanato-1H-pyrazole-5-amine compound, yield is 77%.

The obtained product 1-phenyl-4-thiocyanato-1H-pyrazole-5-amine was structurally analyzed by a nuclear magnetic resonance spectrometer. The results are shown in Figures 7 to 8. Figure 7 is the ¹ H nuclear magnetic resonance ( ¹ H-NMR) spectrum of the 1-phenyl-4-thiocyanato-1H-pyrazole-5-amine product prepared in Example 4 of the present invention; Figure 8 is the implementation of the present invention. ¹³ C nuclear magnetic resonance ( ¹³ C-NMR) spectrum of the 1-phenyl-4-thiocyanato-1H-pyrazole-5-amine product prepared in Example 4. ¹ HNMR (CDCl ₃ , 400MHz, ppm): δ = 7.59 (s, 1H), 7.55-7.50 (m, 4H), 7.46-7.42 (m, 1H), 4.50 (br, 2H); ¹³ C NMR (CDCl ₃ , 100MHz, ppm): δ = 148.1, 143.5, 137.7, 129.8, 128.6, 123.9, 111.0, 77.7.

Example 5

Put 3-methyl-1-(p-methyl)phenyl-1H-pyrazole-5-amine (0.3mmoL, 56.1mg) and potassium thiocyanate (0.6mmol, 58.3 mg), acetic acid (0.3mmol, 18.2mg), acetonitrile (2.5mL) and water (0.5mL). The platinum electrode serves as both anode and cathode. The reaction is stirred by electricity (I=5mA) at room temperature and followed by TLC detection. . After the reaction is completed, the residue obtained is spin-dried and passed through a chromatographic column using an ethyl acetate/petroleum ether system as the eluent to obtain the product 3-methyl-1-(p-methyl)phenyl-4-thiocyanate-1H. - Pyrazol-5-amine compound, yield 85%.

The obtained product 3-methyl-1-(p-methyl)phenyl-4-thiocyanato-1H-pyrazole-5-amine was structurally analyzed by a nuclear magnetic resonance spectrometer. The results are shown in Figures 9 to 10. Figure 9 is ^{the 1} H nuclear magnetic resonance ( ¹ H-NMR) of the 3-methyl-1-(p-methyl)phenyl-4-thiocyanato-1H-pyrazole-5-amine product prepared in Example 5 of the present invention. ) spectrum; Figure 10 is the ¹³ C NMR ( ¹³ C-NMR) spectrum. ¹ H NMR (CDCl ₃ , 400MHz, ppm): δ = 7.35-7.32 (m, 2H), 7.28 (d, J = 8.0Hz, 2H), 4.43 (br, 2H), 2.40 (s, 3H), 2.32 (s, 3H); ¹³ C NMR (CDCl ₃ , 100MHz, ppm): δ = 151.4, 148.4, 138.3, 135.1, 130.2, 123.8, 111.0, 76.8, 21.1, 12.1.

Example 6

Put tert-butyl-5-amino-3-methyl-1H-pyrazole-1-carboxylate (0.3mmoL, 59.1mg) and potassium thiocyanate (0.6mmol, 58.3mg), acetic acid (0.3mmol, 18.2mg), acetonitrile (2.5mL) and water (0.5mL). The platinum electrode serves as both anode and cathode. The reaction is stirred by electricity (I=5mA) at room temperature and followed by TLC. detection. After the reaction is completed, the residue obtained is spin-dried and passed through a chromatographic column using an ethyl acetate/petroleum ether system as the eluent to obtain the product tert-butyl-5-amino-3-methyl-4-thiocyanate-1H- Pyrazole-1-carboxylate compound, yield 54%.

The structure of the obtained product tert-butyl-5-amino-3-methyl-4-thiocyanato-1H-pyrazole-1-carboxylate was analyzed using a nuclear magnetic resonance spectrometer. The results are shown in Figures 9 to 10. Figure 9 is the ¹ H NMR ( ¹ H- NMR) spectrum; Figure 10 is the ¹³ C NMR of the tert-butyl-5-amino-3-methyl-4-thiocyanate-1H-pyrazole-1-carboxylate product prepared in Example 5 of the present invention. Resonance ( ¹³ C-NMR) spectrum. ¹ H NMR (CDCl ₃ , 400MHz, ppm): δ = 6.05 (br, 2H), 2.30 (s, 3H), 1.65 (s, 9H); ¹³ C NMR (CDCl ₃ , 100MHz, ppm): δ = 154.0 ,153.3,149.8,110.1,86.6,76.5,27.9,12.5.

The reaction time of electrification and stirring in the embodiment of the present invention can be arbitrary. As long as the electrification is applied, 5-aminopyrazole-4-thiocyanate compounds can be prepared. The optimal electrification time is about 5 hours, and the yield of the obtained product is the highest. . 5-Aminopyrazole-4-thiocyanate compounds can be prepared at any other time, but the yield will change. From the beginning of power on to 5h, the yield gradually increases, and when it exceeds 5h, the yield decreases. It may be due to the excessively long electrocatalytic time that the generated products are converted into other by-products.

The basic principles and main features of the present invention and the advantages of the present invention have been shown and described above. Those skilled in the industry should understand that the present invention is not limited by the above embodiments. The above embodiments and descriptions only illustrate the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention will also have other aspects. Various changes and modifications are possible, which fall within the scope of the claimed invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims (7)

1. An electrochemical synthesis method of a 5-aminopyrazole-4-thiocyanate compound is characterized by comprising the following steps:

(1) Electrocatalytic reaction: respectively adding thiocyanate, 5-aminopyrazole compounds, acid and solvent into a reaction tank, installing a catalytic electrode, and electrifying and stirring for reaction;

(2) And (3) separating and purifying: separating and purifying the solution after the electrocatalytic reaction is completed to obtain a 5-aminopyrazole-4-thiocyanate compound;

the 5-aminopyrazole-4-thiocyanate compound has a structure shown as follows:

wherein R is ¹ Is hydrogen, C ₁ ～C ₅ Alkyl, aryl;R ² is aryl or ester;

the thiocyanate is one of potassium thiocyanate, ammonium thiocyanate and sodium thiocyanate;

the 5-aminopyrazole compound has a structure shown as follows:

wherein R is ¹ Is hydrogen, C ₁ ～C ₅ Alkyl, aryl; r is R ² Is aryl or ester;

the solvent is acetonitrile and water;

the current i=5ma of the energized stirring reaction.

2. The electrochemical synthesis method according to claim 1, wherein: the mass ratio of the 5-aminopyrazole compound to the thiocyanate is 1:1-1:4.

3. The electrochemical synthesis method according to claim 1, wherein: the initial concentration of the 5-aminopyrazole compound is 0.05-0.2 mol/L.

4. The electrochemical synthesis method according to claim 1, wherein: the acid is one of acetic acid, benzoic acid, hydrochloric acid, sulfuric acid and diphenyl phosphoric acid, and the mass of the acid is 30-120% of that of the 5-aminopyrazole compound.

5. The electrochemical synthesis method according to claim 1, wherein: the temperature of the stirring reaction is 0-80 ℃.

6. The electrochemical synthesis method according to claim 1, wherein: the electrode is a conventional commercial electrode material.

7. The electrochemical synthesis method according to claim 1, wherein: the separation and purification method is one of column chromatography, liquid chromatography, distillation and recrystallization.