Electrochemical preparation of 3,4-dibromopyrazoles

Abstract

The application belongs to the technical field of organic electrochemical synthesis, and particularly relates to an electrochemical preparation method of 3,4-dibromopyrazole. The application uses 3,4,5-tribromopyrazole as a substrate, and effectively alleviates the problems of low stability and easy ring opening of pyrazole by adjusting the substrate concentration, cathode and anode electrode materials and electrolytic potential. The yield of prepared 3,4-dibromopyrazole is higher than 60%, which is much higher than the synthesis yield of the current 3,4-dibromopyrazole debromination synthesis method in the background technology, and the preparation process is simpler. The application increases 3-bromopyrazole, and 3,4,5-tribromopyrazole is electrochemically reduced and debrominated at the cathode to generate 3,4-dibromopyrazole and bromide ions. The bromide ions lose electrons and are electrooxidized to bromine at the anode, and the bromine reacts with 3-bromopyrazole to generate 3,4-dibromopyrazole.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic electrochemical synthesis, and particularly relates to a method for preparing 3,4-dibromopyrazole by selective electrochemical reduction debromination of 3,4,5-tribromopyrazole in a diaphragm-free electrolytic cell and using paired electro-synthesis technology. BACKGROUND

[0002] As a five-membered heterocyclic compound containing two nitrogen atoms, pyrazole has wide chemical, biological, pesticide and pharmacological properties. Different pyrazole derivatives, especially different halogenated pyrazoles, have various biological activities such as anticancer, antiviral, antibacterial, antituberculosis and anti-inflammatory. Therefore, structural modification of pyrazole is of great significance for the development of new drugs and functional materials. Halogenated pyrazole compounds can provide more reaction sites, effectively expand the diversity of product synthesis, and be applied in the fields of medicine development, pesticide and agricultural chemistry, material science and organic synthesis chemistry. Among them, brominated pyrazole derivatives are usually used as pre-functionalized products of pyrazole. However, brominated pyrazole derivatives still have defects such as complex synthesis steps and poor controllability of bromine substitution sites. Therefore, developing an efficient synthesis method of brominated pyrazole derivatives has become a technical problem to be solved in the field.

[0003] Among the brominated derivatives of pyrazole, there is no mature synthesis method for 3,4-dibromopyrazole. At present, 3,4-dibromopyrazole is mainly synthesized by chemical debromination of 3,4,5-tribromopyrazole and direct bromination of pyrazole. The main steps of the chemical debromination of 3,4,5-tribromopyrazole include: ① introducing a temporary protecting group (vinyl group) at position 1; ② using strong reducing agents such as alkyl lithium / Grignard reagent to debrominate at position 5; the bromine ion at position 4 is retained due to steric hindrance and electronic effect; ③ removing the protecting group by washing with potassium permanganate. This multi-step synthesis method needs to frequently handle intermediate products, resulting in a total yield of less than 60%, and side reactions occur, the product purity is not high, and a large amount of organic waste liquid is generated. In the direct bromination of pyrazole, if bromine molecules are used for direct bromination, the bromination degree is difficult to control, and 3,4,5-tribromopyrazole is easily generated, so that the selectivity of 3,4-dibromopyrazole is not high. Selecting a specific halogenating agent (such as N,N-dibromo-5,5-dimethylhydantoin) can improve the selectivity of 3,4-dibromopyrazole, but the synthesis steps of the halogenating agent are complicated, and the yield is low, which is not suitable for large-scale industrial production.

[0004] Electrochemical reductive dehalogenation technology is a current research hotspot, and its core is to precisely control the matching relationship between the reduction potential of the reactant and the hydrogen evolution overpotential of the electrolyte, so as to realize high-selectivity dehalogenation. This technology has been successfully applied to the selective debromination of brominated aliphatic rings and brominated sulfur-containing heterocycles. For example, patent CN104087968A discloses that a halogenated pyridine similar to a pyrazole structure is used as a substrate, a diaphragm tank electrochemical preparation process is adopted, the system is adjusted to be an acidic solution, and high-selectivity dehalogenation is realized at the cathode. However, the debromination reaction of brominated heterocyclic compounds such as brominated pyridine often needs to rely on a diaphragm tank, and the six-membered ring structure is usually relatively stable and will only be opened under the action of strong oxidizing acids and other harsh conditions. In comparison, the pyrazole contains two adjacent nitrogen atoms, and the electron cloud density distribution in the ring is more uneven, so its stability is much lower than that of aliphatic ring, thiophene, pyridine, imidazole and other ring compounds. More importantly, the bond energy of the N-N bond on the pyrazole ring is lower than that of the C-Br bond, which causes the pyrazole ring to be opened in a certain natural environment, and the ring is more likely to be opened due to the breaking of the N-N bond under electrochemical conditions, so it is difficult to prepare 3,4-dibromopyrazole with high yield by an electrochemical process. SUMMARY

[0005] The purpose of the present application is to provide an electrochemical preparation method of 3,4-dibromopyrazole with high yield, which is realized by the following technical scheme:

[0006] An electrochemical preparation method of 3,4-dibromopyrazole, characterized in that a diaphragm-free electrolytic tank is used as a reactor, an anode, a cathode and a reference electrode are introduced into an electrolyte containing 3,4,5-tribromopyrazole, electrolysis is carried out, 3,4,5-tribromopyrazole is caused to be electrochemically reduced and debrominated at the cathode to generate 3,4-dibromopyrazole and bromine ions (Br - ); the concentration of 3,4,5-tribromopyrazole in the electrolyte is 10-40 mmol / L; the cathode material includes at least one of brass and silver; and the electrolytic potential is-1.1 to-1.25 V.

[0007] As a preference, the electrolyte further contains 3-bromopyrazole, and the preparation method further includes causing the Br - to be oxidized at the anode to form bromine molecules (Br2), and causing 3-bromopyrazole to react with Br2 to generate 3,4-dibromopyrazole.

[0008] As a preference, the concentration of 3-bromopyrazole in the electrolyte is 5-50 mmol / L.

[0009] As a preference, 0.04 mol / L-0.001 mol / L H2SO4 is further added to the electrolyte.

[0010] Preferably, the solvent of the electrolyte is N,N-dimethylformamide and water in a volume ratio of (5-9):(5-1).

[0011] Preferably, the anode comprises at least one of platinum, carbon rod and titanium sheet; the reference electrode is saturated calomel electrode.

[0012] Preferably, the supporting electrolyte in the electrolyte is one or more of tetrabutylammonium perchlorate, lithium perchlorate and tetrabutylammonium hexafluorophosphate.

[0013] Preferably, in the electrolysis process, the temperature of the electrolyte is 40-60℃, and the rotation speed is 600-900 rpm.

[0014] Preferably, the cathode material is commercially available brass sheet; the anode material is carbon rod; the reference electrode is saturated calomel electrode; the solvent of the electrolyte is N,N-dimethylformamide and water in a volume ratio of 7:3; the supporting electrolyte in the electrolyte is tetrabutylammonium perchlorate; and the electrolysis condition is that the temperature is 50℃, the potential is-1.15V, the rotation speed is 700 rpm, and the electrolysis time is 10 hours.

[0015] Compared with the prior art, the present application has the following beneficial effects:

[0016] The present application uses 3,4,5-tribromopyrazole as a reaction substrate, effectively alleviates the problems of low stability and easy ring opening of pyrazole by adjusting the substrate concentration, cathode electrode material and electrolysis potential, and the yield of 3,4-dibromopyrazole prepared is higher than 60%, which is much higher than the synthesis yield of the current 3,4,5-tribromopyrazole debromination synthesis method in the background technology, and the preparation process is simpler. More importantly, it is known to those skilled in the art that when a diaphragmless electrolytic cell is used as a reactor, Br - is generated by cathodic reduction debromination, and Br2 is oxidized into Br2 at the anode, and Br2 will undergo a substitution reaction with the debromination product 3,4-dibromopyrazole to regenerate 3,4,5-tribromopyrazole, thereby reducing the yield of 3,4-dibromopyrazole. However, performance tests show that under the same potential, the conversion rate of 3,4,5-tribromopyrazole in a diaphragmless electrolytic cell is much higher than that in a diaphragm electrolytic cell, and the yield of 3,4-dibromopyrazole is more than doubled, which embodies unexpected technical effects. When the reaction substrate 3,4,5-tribromopyrazole and 3-bromopyrazole are added at the same time in the cathode chamber of the diaphragm electrolytic cell, no bromination reaction of 3-bromopyrazole occurs.

[0017] Further, by adding 3-bromopyrazole, 3,4,5-tribromopyrazole undergoes electrochemical reduction debromination at the cathode to generate 3,4-dibromopyrazole and Br - , Br -The anode loses electrons and is oxidized to Br2, which reacts with 3-bromopyrazole to form 3,4-dibromopyrazole. The present concept effectively improves the yield of 3,4-dibromopyrazole by allowing the two raw materials to be converted into the same target product at the cathode and anode respectively through paired electro-synthesis; on the other hand, Br - is reused by being converted into active bromine through anodic oxidation, reducing the Br - residual in the electrolyte, thereby blocking the environmental pollution problems caused by it. BRIEF DESCRIPTION OF DRAWINGS

[0018] The drawings will be briefly introduced as follows:

[0019] Figure 1 is the synthesis route of 3,4-dibromopyrazole;

[0020] Figure 2 is the liquid chromatogram of the electrolyte when 3,4,5-tribromopyrazole and 3-bromopyrazole are used as the reaction substrates based on Example 2 and Example 14;

[0021] Figure 3 is the liquid chromatogram of the electrolyte of Example 2 in a diaphragm-free electrolytic cell and the electrolyte of Comparative Example 10 in a diaphragm-containing electrolytic cell. DETAILED DESCRIPTION

[0022] The present application will be further described in the form of specific examples. Those skilled in the art will be able to implement the present application based on these descriptions. In addition, the examples of the present application involved in the following descriptions are generally only a part of the examples of the present application, not all the examples. Therefore, all other examples obtained by those skilled in the art based on the examples in the present application without making creative efforts should belong to the scope of protection of the present application.

[0023] In the following examples, (III) is 3,4-dibromopyrazole, and (IV) is by-product 4-bromopyrazole.

[0024] Example 1

[0025] A preparation method of 3,4-dibromopyrazole, comprising the following steps:

[0026] In a 30 mL capacity electrolysis cell without diaphragm, 0.228 g (30 mmol / L) 3,4,5-tribromopyrazole, 0.067 g (20 mmol / L) 3-bromopyrazole, 0.428 g (50 mmol / L) supporting electrolyte TBAP, 100 uL 1 mol / L H2SO4 solution, 17.5 mL DMF and 7.5 mL deionized water as solvent (volume ratio 7:3), 50 °C, using commercially available brass sheet (2 cm x 2 cm) and C rod as cathode and anode respectively, the rotation speed is 700 rpm, the reaction is carried out by the method of paired electro-synthesis at -1.15 V for 10 h. The reaction product is analyzed by liquid chromatograph, and the yield of the target product is calculated by area normalization method.

[0027] Examples 2-9

[0028] The reaction steps and reaction processes of examples 2-9 are the same as example 1, except that different concentrations of 3-bromopyrazole are added, which are 0 mmol / L (example 2), 5 mmol / L (example 3), 10 mmol / L (example 4), 15 mmol / L (example 5), 25 mmol / L (example 6), 30 mmol / L (example 7), 40 mmol / L (example 8) and 50 mmol / L (example 9) for electrolysis experiments, and the results are listed in Table 1.

[0029] Table 1 Effect of different concentrations of 3-bromopyrazole on the electrochemical reduction of 3,4,5-tribromopyrazole

[0030]

[0031] As can be seen from Table 1, the addition of different concentrations of 3-bromopyrazole can directly affect the yield of 3,4,5-tribromopyrazole electrochemically reduced to 3,4-dibromopyrazole. In a single-chamber electrolysis cell, Br - will be electro-oxidized at the anode to generate Br2, which can react with the product 3,4-dibromopyrazole to regenerate the raw material 3,4,5-tribromopyrazole, thereby inhibiting the smooth progress of dehalogenation reaction. However, by adding 3-bromopyrazole to the system, 3-bromopyrazole can preferentially react with Br2 to generate 3,4-dibromopyrazole, which not only improves the yield of 3,4-dibromopyrazole, but also speeds up the reaction rate. Compared with the method without adding 3-bromopyrazole, the Faraday efficiency can be effectively improved. However, too high concentration of 3-bromopyrazole can also lead to a decrease in the yield of the target product. The yield is highest when the concentration of 3-bromopyrazole is 20 mmol / L, so the concentration of 3-bromopyrazole is preferably 20 mmol / L.

[0032] Examples 10, 11 and Comparative Examples 1-3

[0033] The reaction steps and reaction process are the same as in Example 2, except that the cathode is changed to Cu (Example 10), Ag (Example 11), Ni (Comparative Example 1), GC (Comparative Example 2), and Pt (Comparative Example 3) for electrolysis experiments, and the results are listed in Table 2.

[0034] Table 2 Influence of different cathode materials on the electrochemical reduction of 3,4,5-tribromopyrazole

[0035]

[0036] As shown in Table 2, different cathode materials have a great influence on the yield of 3,4,5-tribromopyrazole electrochemically reduced to 3,4-dibromopyrazole. The conversion rate of 3,4,5-tribromopyrazole is higher on an Ag electrode, but the selectivity for 3,4-dibromopyrazole is not high, because of excessive debromination to generate 4-bromopyrazole, and Ag is a noble metal, which is slightly insufficient in economy for industrial production and application. The conversion rate of the reaction substrate is slightly lower on a commercially available brass sheet, but the yield of the target product 3,4-dibromopyrazole is higher, and has better selectivity, so the commercially available brass sheet is preferred as the cathode material.

[0037] Examples 13 and 14

[0038] The reaction steps and reaction process are the same as in Example 2, except that the anode is changed to Pt (Example 13) and Ti (Example 14) for electrolysis experiments, and the results are listed in Table 3.

[0039] Table 3 Influence of different anode materials on the electrochemical reduction of 3,4,5-tribromopyrazole

[0040]

[0041] As shown in Table 3, the anode material also has a certain influence on the electrochemical reduction of 3,4,5-tribromopyrazole to 3,4-dibromopyrazole. On a Pt electrode, the oxygen evolution potential is higher, which is conducive to the oxidation reaction of the reaction substrate at the anode, improving the conversion rate of 3,4,5-tribromopyrazole, but part of the reaction substrate is lost. In Example 14, when the anode is Ti, hydroxyl radicals are easily generated on the Ti electrode, which on the one hand causes the reaction substrate to undergo ring expansion degradation, and on the other hand prevents the bromide ions in the solution from generating active bromine at the anode, so even if 3-bromopyrazole is added, no bromination reaction occurs, so there is still a large amount of 3-bromopyrazole in the system. The yield of the target product is also higher on a C electrode, and the loss of the reaction substrate is less, and C is obviously better than Pt in economy, so the anode is preferably C. When the anode is C and Ti, respectively, and the reaction substrate is 3,4,5-tribromopyrazole and 3-bromopyrazole, the liquid phase analysis spectrum of the electrolysis product is shown in FIG. 2. Figure 2 .

[0042] Examples 15 to 17 and Comparative Example 4

[0043] The reaction procedure and reaction process were the same as Example 2, except that the ratio of DMF to water was different, which was 8:2 (Example 15), 6:4 (Example 16), 5:5 (Example 17), 9:1 (Comparative Example 4), respectively. The results are shown in Table 4.

[0044] Table 4 Effect of different volume ratio of DMF to water on the electro-reduction of 3,4,5-tribromopyrazole

[0045]

[0046] As shown in Table 4, the yield of the product 3,4-dibromopyrazole was different when the ratio of DMF to water was different. 3,4,5-Tribromopyrazole was easily soluble in DMF, but hardly soluble in water. However, water could provide hydrogen ions required for the reaction. Too low ratio of DMF could result in insufficient solubility of the raw material, which hindered the reaction, while too high ratio of DMF could result in insufficient concentration of hydrogen ions, which hindered the de-bromination and hydrogenation reaction. In the absence of 3-bromopyrazole, the yield of the target product could also reach 75.3% when the volume ratio of DMF to water was 7:3.

[0047] Examples 18-20 and Comparative Example 5

[0048] The reaction procedure and reaction process were the same as Example 2, except that the concentration of the reaction substrate was different, which was 10 mmol / L (Example 18), 20 mmol / L (Example 19), 40 mmol / L (Example 20), 50 mmol / L (Comparative Example 5), respectively. The results are shown in Table 5.

[0049] Table 5 Effect of different concentration of 3,4,5-tribromopyrazole on the electro-reduction

[0050]

[0051] As shown in Table 5, the yield of 3,4-dibromopyrazole was affected by the concentration of 3,4,5-tribromopyrazole. When the concentration of the reaction substrate was low, excessive reduction could occur to generate 4-bromopyrazole, while too high concentration of the reaction substrate could result in incomplete reaction. When the concentration of 3,4,5-tribromopyrazole was 30 mmol / L, the yield of the target product was the highest, and therefore, the concentration of 3,4,5-tribromopyrazole was preferably 30 mmol / L.

[0052] Examples 21, 22 and Comparative Example 6

[0053] The reaction steps and reaction process are the same as in Example 2, except that the supporting electrolyte is LiClO4 (Example 21), TBAPF6 (Example 22), and NaBF4 (Comparative Example 6) respectively, and the electrolysis results are shown in Table 6.

[0054] Table 6 Influence of different supporting electrolytes on the electro-reduction of 3,4,5-tribromopyrazole

[0055]

[0056] As can be seen from the results in Table 6, different supporting electrolytes have a greater impact on the yield of 3,4-dibromopyrazole. When TBAP is used as the supporting electrolyte, the yield of the target product is the highest, which is probably because TBAP has better solubility in organic systems, so the preferred supporting electrolyte is TBAP.

[0057] Examples 23-25 and Comparative Example 7

[0058] The reaction steps and reaction process are the same as in Example 2, except that the electrolysis potential is -1.1 V (Example 23), -1.2 V (Example 24), -1.25 V (Example 25), and -1.05 V (Comparative Example 7) respectively, and the electrolysis results are shown in Table 7.

[0059] Table 7 Influence of different electrolysis potentials on the electro-reduction of 3,4,5-tribromopyrazole

[0060]

[0061] As can be seen from Table 7, as the electrolysis potential increases, the yield of the target product 3,4-dibromopyrazole first increases and then decreases. When the potential is low, the reaction is incomplete and the conversion rate of the reaction substrate is low. When the potential is too high, excessive debromination occurs to generate by-products such as 4-bromopyrazole, which reduces the selectivity of the target product. When the electrolysis potential is -1.15 V, the conversion rate of the reaction substrate can reach 89.6% without the addition of 3-bromopyrazole, so the preferred electrolysis potential is -1.15 V.

[0062] Example 26 and Comparative Examples 8 and 9

[0063] The reaction steps and reaction process are the same as in Example 2, except that different concentrations of sulfuric acid solution are added to adjust the pH of the solution, and the concentration of H2SO4 added is 10 mmol / L (Example 26), 0 mmol / L (Comparative Example 8), and 1 mmol / L (Comparative Example 9) respectively for electrolysis experiments, and the results are shown in Table 8.

[0064] Table 8 Influence of different pH values on the electro-reduction of 3,4,5-tribromopyrazole

[0065]

[0066] From the results in Table 8, it can be seen that the addition of a certain amount of acid is conducive to the de-bromination hydrogenation reaction, and the acid has a wide range of adaptation. When the concentration of H2SO4 is higher than 4 mmol / L, the yield of the target product 3,4-dibromopyrazole is relatively high. However, too high concentration of acid will corrode the electrode and facilitate the hydrogen evolution reaction, which is easy to further de-brominate, thereby reducing the selectivity of the target product 3,4-dibromopyrazole, so the concentration of H2SO4 is preferably 4 mmol / L.

[0067] Comparative Example 10

[0068] The reaction steps and reaction process are the same as in Example 2, except that an H-type diaphragm electrolytic cell is used, and the electrolysis results are listed in Table 9.

[0069] Table 9 Electro-reduction reaction of 3,4,5-tribromopyrazole in different electrolytic cells

[0070]

[0071] From the above table, it can be seen that without the addition of 3-bromopyrazole, in the diaphragm-free electrolytic cell, the Br - generated by de-bromination on the cathode is easily oxidized to Br2, and Br2 will react with the de-bromination product 3,4-dibromopyrazole to regenerate 3,4,5-tribromopyrazole, thereby reducing the yield of 3,4-dibromopyrazole. Under the same potential, the conversion rate of 3,4,5-tribromopyrazole in the diaphragm-free electrolytic cell is much higher than that in the diaphragm electrolytic cell, and the yield of 3,4-dibromopyrazole is also significantly improved, which embodies the unexpected technical effect.

[0072] Comparative Example 11

[0073] The reaction steps and reaction process are the same as in Example 1, except that an H-type diaphragm electrolytic cell is used, and the electrolysis results are listed in Table 10.

[0074] Table 10 Electro-reduction reaction of 3,4,5-tribromopyrazole in different electrolytic cells

[0075]

[0076] From Table 10, it can be seen that when the diaphragm-free electrolytic cell is used as the reactor, the Br -When the anode is oxidized to Br2, Br2 preferentially reacts with 3-bromopyrazole to also produce 3,4-dibromopyrazole, thereby increasing the yield of 3,4-dibromopyrazole. Comparative Example 11 shows that, under otherwise identical conditions, in a diaphragm electrolysis cell, the migration of bromide ions is limited, the anode cannot be oxidized to Br2, and the reactions in the anode compartment and the cathode compartment cannot be linked, so in the diaphragm electrolysis cell, the addition of 3-bromopyrazole has little effect on the conversion rate of 3,4,5-tribromopyrazole and the yield of the target product 3,4-dibromopyrazole (Comparative Examples 11 and 10).

Claims

1. A method for the electrochemical preparation of 3,4-dibromopyrazole, characterized in that, The diaphragmless electrolytic tank is used as a reaction medium, an anode, a cathode and a reference electrode are introduced into an electrolyte containing 3,4,5-tribromopyrazole, electrolysis is carried out, 3,4,5-tribromopyrazole is electrochemically reduced and debrominated at the cathode to generate 3,4-dibromopyrazole and bromide ions; the concentration of 3,4,5-tribromopyrazole in the electrolyte is 10-40 mmol / L; the cathode material comprises at least one of copper and silver; and the electrolytic potential is-1.1 to-1.25 V.

2. A process for the preparation of 3,4-dibromopyrazole according to claim 1, characterized in that, The electrolyte further contains 3-bromopyrazole, and the preparation method further comprises: causing the bromide ions to be oxidized to form bromine at the anode, and causing 3-bromopyrazole to react with the bromine to generate 3,4-dibromopyrazole.

3. A process for the preparation of 3,4-dibromopyrazole according to claim 2, characterized in that, The concentration of 3-bromopyrazole in the electrolyte is 1-50 mmol / L.

4. The method for preparing 3,4-dibromopyrazole according to claim 1, characterized in that, The electrolyte further contains 0.04 mol / L-0.001 mol / L H2SO4.

5. The method for preparing 3,4-dibromopyrazole according to claim 1, characterized in that, The solvent of the electrolyte is N,N-dimethylformamide and water in a volume ratio of (5-8):(2-5).

6. The method for preparing 3,4-dibromopyrazole according to claim 1, characterized in that, The anode comprises at least one of platinum, a carbon rod and a titanium sheet; and the reference electrode is a saturated calomel electrode.

7. The method for preparing 3,4-dibromopyrazole according to claim 1, characterized in that, The supporting electrolyte in the electrolyte is one or more of tetrabutylammonium perchlorate, lithium perchlorate and tetrabutylammonium hexafluorophosphate.

8. The method for preparing 3,4-dibromopyrazole according to claim 1, characterized in that, The electrolysis conditions are: a temperature of 40-60 ℃ and a rotation speed of 600-900 rpm.

9. The method for preparing 3,4-dibromopyrazole according to claim 2, characterized in that, The cathode material is copper; the anode material is a carbon rod; the reference electrode is a saturated calomel electrode; the solvent of the electrolyte is N,N-dimethylformamide and water in a volume ratio of 7:3; the supporting electrolyte in the electrolyte is tetrabutylammonium perchlorate; and the electrolysis conditions are: a temperature of 50 ℃, a potential of-1.15 V, a rotation speed of 700 rpm, and an electrolysis time of 10 h.

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