CN115522219B - A preparation method of 4-bromopyrazole compounds - Google Patents

Abstract

The invention discloses a preparation method of a 4-bromopyrazole compound, which comprises the following steps: hydrazine, 1, 3-propanediol and diethyl 2-bromomalonate are placed in an organic solvent, two electrodes are placed in a reaction liquid, constant current electrolysis is carried out, and after the reaction is finished, the 4-bromopyrazole compound is obtained through aftertreatment. The method belongs to a multi-component reaction, realizes the construction of a plurality of chemical bonds in one-step reaction, and avoids complex post-treatment and resource waste. The invention uses electrons as cleaning agent, avoiding the use of a large amount of oxidizing agent; meanwhile, the diethyl 2-bromomalonate with higher oxidation state is used as a brominating reagent, so that no peroxidation effect exists, and the use of excessive brominating reagent is avoided. The invention does not need to use transition metal catalyst and ligand or a large amount of redox agents, has the advantages of mild reaction condition, simple operation, low cost of raw materials, wide application range and the like, has a certain application prospect, and provides a green novel method for preparing 4-bromopyrazole compounds.

Description

A preparation method of 4-bromopyrazole compounds

Technical Field

The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 4-bromopyrazole compounds by a multi-component "one-pot method" under electrochemical promotion.

Background technique

The basic configuration of pyrazole derivatives is widely present in natural products and drug molecules, and is of great significance to medicinal chemistry and materials science. Therefore, their construction and functionalization have attracted great attention from synthetic organic chemists. Among the numerous pyrazole derivatives, 4-bromopyrazole compounds not only exhibit a wide range of biological and pharmaceutical activities, but can also be used as universal synthetic intermediates for synthetic transformations.

At present, the reported methods for preparing 4-bromopyrazole compounds mainly include oxidative bromination reaction using sodium bromide as bromine source, bromination reaction using bromine as bromine source, photocatalytic bromination reaction and electrocatalytic bromination reaction. In 2017, MacKay's research group reported the preparation of 4-bromopyrazole compounds by bromination reaction promoted by excess potassium peroxymonosulfonate (oxone) oxidant using sodium bromide as bromination reagent. This method requires the use of excess oxidant, which does not meet the requirements of atom economy. Bromination reactions using bromine as bromine source have also been reported, such as invention patent WO2007058832, which discloses a method for preparing 4-bromopyrazole compounds using bromine as bromination reagent. This method uses highly corrosive and toxic bromine as bromination reagent, which is not suitable for industrial production. In 2018, Koenig's research group reported a method for preparing 4-bromopyrazole compounds by bromination reaction of pyrazole under visible light promotion using sodium bromide as bromination source. However, this method requires the use of special photocatalysts, which is costly. In 2019, Lei Aiwen's research group reported a method for preparing 4-bromopyrazole compounds by electrochemically promoted bromination of pyrazole derivatives. This method uses cheap sodium bromide as a bromine source and electricity as a clean energy source to achieve the bromination reaction of pyrazole derivatives under mild reaction conditions. However, due to the low oxidation state of bromide ions, peroxidation is easily caused on the anode surface, so the reaction requires the use of 2-4 equivalents of brominating agent to make the reaction proceed effectively.

In summary, the reported methods for preparing 4-bromopyrazole compounds all use pyrazole as the starting material, and a multi-component "one-pot" cyclobromination method has not yet been reported. In addition, the above reactions all have certain limitations, such as high toxicity of the reagents used, serious environmental pollution, complex post-treatment, expensive reagents, and low bromination rate.

Summary of the invention

In view of the above-mentioned deficiencies in the prior art, the purpose of the present invention is to provide a method for preparing 4-bromopyrazole compounds, which solves the problems that the existing methods require the use of a large amount of oxidants, toxic and harmful reagents or special metal catalysts, as well as complex operations and serious environmental pollution.

In order to solve the above technical problems, the present invention adopts the following technical solutions:

A method for preparing a 4-bromopyrazole compound, characterized in that it comprises the following steps: placing a hydrazine compound (1), a 1,3-propanedione compound (2), diethyl 2-bromomalonate (3) and an electrolyte in an organic solvent to obtain a reaction solution, then placing two electrodes in the reaction solution for constant current electrolysis, and after sufficient reaction, post-processing to obtain a 4-bromopyrazole compound (4);

Wherein R ¹ is H, alkyl, aryl or aromatic heterocycle; R ² and R ³ are both alkyl or aryl.

Furthermore, R ¹ is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, or halogen-substituted C ₁ -C ₃ alkyl.

Further, R ¹ is a C ₁ -C ₃ alkyl group, an aryl group, a C ₁ -C ₃ alkyl substituted aryl group, or a halogen substituted aryl group;

^R2 is halogen, _C1 - _C3 alkyl, halogen-substituted _C1 - _C3 alkyl or _C1 - _C3 alkoxy;

R ³ is halogen, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy.

Furthermore, the molar ratio of the hydrazine compound, the 1,3-propanedione compound and diethyl 2-bromomalonate is 1-3:1:1-3.

Furthermore, the post-treatment includes the following steps: after the reaction is completed, the reaction solution is concentrated under reduced pressure to remove the solvent, and the residue is separated by column chromatography to obtain 4-bromopyrazole compounds; the elution solvent in the column chromatography is ethyl acetate/petroleum ether.

Furthermore, the reaction temperature is 25 to 80° C. and the reaction time is 10 to 24 hours.

Furthermore, the constant current intensity is 2-30 mA.

Furthermore, the electrode is one or two of platinum sheet, graphite sheet, copper sheet, stainless steel, nickel sheet, aluminum sheet, foamed nickel or foamed aluminum.

Furthermore, the electrolyte is one or more of tetrabutylammonium tetrafluoroborate, tetraethylammonium tetrafluoroborate, potassium tetrafluorophosphate, lithium perchlorate, potassium iodide, ammonium bromide, tetrabutylammonium iodide, tetraethylammonium hexafluorophosphate, tetraethylammonium perchlorate, and sodium hexafluorophosphate.

Furthermore, the organic solvent is one or more of acetonitrile, acetone, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, dichloroethane, dichloromethane, and toluene.

Among them, hydrazine compounds and 1,3-propanedione compounds are widely available and inexpensive, so they are selected as the raw materials.

Compared with the prior art, the present invention has the following beneficial effects:

1. The preparation method of the present invention uses hydrazine, 1,3-propanedione and diethyl 2-bromomalonate as raw materials. Under electrolytic conditions, a pyrazole compound is first obtained by a cyclization reaction, and then a 4-bromopyrazole compound is generated by electrocatalytic bromination. The reaction is a multi-component "one-pot" reaction, and three new chemical bonds are formed simultaneously in one step. Compared with the step-by-step reaction, the multi-component reaction has higher efficiency and avoids the complicated post-processing process.

2. The method for preparing 4-bromopyrazole compounds of the present invention uses electrons as a cleaning agent, avoiding the use of a large amount of oxidants; using diethyl 2-bromomalonate as a brominating agent, compared with the method of using sodium bromide as a bromine source, diethyl 2-bromomalonate has a higher oxidation state and is difficult to be anodic oxidized, thereby avoiding the overoxidation effect and reducing the amount of the brominating agent, and only using one equivalent of the brominating agent can efficiently obtain 4-bromopyrazole compounds. In addition, the present invention does not need to use a transition metal catalyst and a ligand or a large amount of redox agents, has the advantages of mild reaction conditions, simple operation, cheap raw materials, and a wide range of applications, has excellent application prospects, and provides a green new method for the preparation of 4-bromopyrazole compounds.

Detailed ways

The present invention is further described in detail below with reference to the examples. The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and raw materials described can be obtained from commercial sources and/or prepared according to known methods unless otherwise specified.

Example 1

Phenylhydrazine (1a, 0.5mmol), acetylacetone (2a, 0.5mmol), diethyl 2-bromomalonate ( ₃ , 0.5mmol), ^nBu4NBF4 (0.5mmol) and _6mL of acetonitrile were placed in a non-separation electrolytic cell, with platinum electrodes (Pt) as anode and cathode, and electrolyzed at room temperature and 10mA constant current for 12h. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/petroleum ether) to obtain the target product 4a (yield: 90%).

The results of nuclear magnetic resonance showed that ¹ HNMR (500 MHz, CDCl ₃ ) δ7.43 (t, J=7.5 Hz, 2H), 7.35 (d, J=7.5 Hz, 4H), 2.27 (s, 7H). ¹³ CNMR (126 MHz, CDCl ₃ ) δ147.53, 137.46, 129.13, 127.77, 124.66, 96.35, 12.32, 11.72. It can be seen that the structure of the obtained product is the target product 4a.

Example 2

The Pt(+)|Cu(-) electrode pair was used instead of the Pt(+)|Pt(-) electrode pair. The other conditions were the same as those in Example 1. The yield of the target product 4a was 84%.

Example 3

The Pt(+)|Ni(-) electrode pair was used instead of the Pt(+)|Pt(-) electrode pair. The other conditions were the same as those in Example 1. The yield of the target product 4a was 88%.

Example 4

The Pt(+)|Al(-) electrode pair was used instead of the Pt(+)|Pt(-) electrode pair. The other conditions were the same as those in Example 1. The yield of the target product 4a was 83%.

Example 5

Tetraethylammonium tetrafluoroborate was used instead of tetrabutylammonium tetrafluoroborate, and the other conditions were the same as those in Example 1. The yield of the target product 4a was 85%.

Example 6

Potassium tetrafluorophosphate was used instead of tetrabutylammonium tetrafluoroborate, and the other conditions were the same as those in Example 1. The yield of the target product 4a was 80%.

Example 7

Lithium perchlorate was used instead of tetrabutylammonium tetrafluoroborate, and the other conditions were the same as those in Example 1. The yield of the target product 4a was 78%.

Example 8

Tetrabutylammonium iodide was used instead of tetrabutylammonium tetrafluoroborate, and the other conditions were the same as those in Example 1. The yield of the target product 4a was 62%.

Example 9

Tetraethylammonium perchlorate was used instead of tetrabutylammonium tetrafluoroborate, and the other conditions were the same as those in Example 1. The yield of the target product 4a was 75%.

Example 10

Acetone was used instead of acetonitrile, and the other conditions were the same as those in Example 1. The yield of the target product 4a was 82%.

Embodiment 11

Ethanol was used instead of acetonitrile, and the other conditions were the same as in Example 1, and the yield of the target product 4a was 65%.

Example 12

Dimethyl sulfoxide was used instead of acetonitrile, and the other conditions were the same as those in Example 1. The yield of the target product 4a was 90%.

Example 13

N,N-dimethylformamide was used instead of acetonitrile, and the other conditions were the same as those in Example 1. The yield of the target product 4a was 79%.

Embodiment 14

The current intensity was replaced by 5 mA instead of 10 mA, and the other conditions were the same as in Example 1. The yield of the target product 4a was 80%.

Embodiment 15

The current intensity was 12 mA instead of 10 mA, and the other conditions were the same as in Example 1. The yield of the target product 4a was 82%.

Example 16

The current intensity was replaced by 20 mA instead of 10 mA, and the other conditions were the same as in Example 1. The yield of the target product 4a was 78%.

Embodiment 17

The reaction temperature was 50°C instead of room temperature, and the other conditions were the same as in Example 1. The yield of the target product 4a was 84%.

Embodiment 18

The reaction time was extended to 24 h, and the other conditions were the same as in Example 1, and the yield of the target product 4a was 88%.

It can be seen from the above examples 1-18 that the best reaction conditions are the reaction conditions of Example 1, that is, Pt(+)|Pt(-) electrodes as electrode pairs, current intensity of 10 mA, electrolyte of tetrabutylammonium tetrafluoroborate, solvent of acetonitrile, reaction temperature of room temperature, and reaction time of 12 h. Under the optimized reaction conditions, the inventors further selected hydrazine and 1,3-propanedione with different substituents as raw materials to develop an efficient method for preparing 4-bromopyrazole compounds.

Embodiment 19

Phenylhydrazine (1a, 0.5mmol), acetylacetone (2a, 0.5mmol), diethyl 2-bromomalonate ( ₃ , 0.5mmol), ^nBu4NBF4 (0.5mmol) and _6mL acetonitrile were placed in a non-separation electrolytic cell, with platinum electrodes (Pt) as anode and cathode, and electrolyzed at room temperature and 10mA constant current for 12h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/petroleum ether) to obtain the target product 4a (yield: 90%).

The results of nuclear magnetic resonance showed that ¹ HNMR (500 MHz, CDCl ₃ ) δ7.43 (t, J=7.5 Hz, 2H), 7.35 (d, J=7.5 Hz, 4H), 2.27 (s, 7H). ¹³ CNMR (126 MHz, CDCl ₃ ) δ147.53, 137.46, 129.13, 127.77, 124.66, 96.35, 12.32, 11.72. It can be seen that the structure of the obtained product is the target product 4a.

Embodiment 20

4-Methylphenylhydrazine (1b, 0.5mmol), acetylacetone (2a, 0.5mmol), diethyl 2- _{bromomalonate} ( ₃ , 0.5mmol), ^nBu4NBF4 (0.5mmol) and 6mL acetonitrile were placed in a non-separation electrolytic cell, with platinum electrodes (Pt) as anode and cathode, and electrolyzed at room temperature and 10mA constant current for 12h. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/petroleum ether) to obtain the target product 4b (yield: 88%).

The results of nuclear magnetic resonance showed that ¹ HNMR (500 MHz, CDCl ₃ )δ7.32-7.20 (m, 4H), 2.40-2.36 (m, 3H), 2.30-2.24 (m, 6H). ¹³ CNMR (126 MHz, CDCl ₃ )δ147.25, 137.77, 137.48, 137.40, 129.68, 124.58, 96.00, 21.07, 12.32, 11.63. It can be seen that the structure of the obtained product is the target product 4b.

Embodiment 21

4-Methoxyphenylhydrazine (1c, 0.5mmol), acetylacetone (2a, 0.5mmol), diethyl 2-bromomalonate ( ₃ , 0.5mmol), ^nBu4NBF4 (0.5mmol) and 6mL _acetonitrile were placed in a non-separation electrolytic cell, with platinum electrodes (Pt) as anode and cathode, and electrolyzed at room temperature and 10mA constant current for 12h. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/petroleum ether) to obtain the target product 4c (yield: 70%).

The results of nuclear magnetic resonance showed that ¹ HNMR (500 MHz, CDCl ₃ ) δ7.44 (t, J=7.5 Hz, 2H), 7.38 (d, J=7.5 Hz, 2H), 2.31 (d, J=2.0 Hz, 6H). ¹³ CNMR (126 MHz, CDCl ₃ ) δ147.59, 139.85, 137.53, 129.17, 127.83, 124.71, 96.38, 12.34, 11.75. It can be seen that the structure of the obtained product is the target product 4c.

Embodiment 22

4-Chlorophenylhydrazine (1d, 0.5mmol), acetylacetone (2a, 0.5mmol), _diethyl 2-bromomalonate ( ₃ , 0.5mmol), ^nBu4NBF4 (0.5mmol) and 6mL acetonitrile were placed in a non-separation electrolytic cell, with platinum electrodes (Pt) as anode and cathode, and electrolyzed at room temperature and 10mA constant current for 12h. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/petroleum ether) to obtain the target product 4d (yield: 88%).

The results of nuclear magnetic resonance showed that ¹ HNMR (500 MHz, CDCl ₃ ) δ7.41 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 2.27 (d, J=5.5 Hz, 6H). ¹³ CNMR (126 MHz, CDCl ₃ ) δ148.00, 138.32, 137.50, 133.52, 129.32, 125.72, 96.82, 12.31, 11.75. It can be seen that the structure of the obtained product is the target product 4d.

Embodiment 23

4-Trifluoromethylphenylhydrazine (1e, 0.5mmol), acetylacetone (2a, 0.5mmol), diethyl 2 _- bromomalonate ( ₃ , 0.5mmol), ^nBu4NBF4 (0.5mmol) and 6mL acetonitrile were placed in a non-separation electrolytic cell, with platinum electrodes (Pt) as anode and cathode, and electrolyzed at room temperature and 10mA constant current for 12h. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/petroleum ether) to obtain the target product 4e (yield: 85%).

The results of nuclear magnetic resonance showed that ¹ HNMR (500 MHz, CDCl ₃ ) δ7.72 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 2.34 (s, 3H), 2.31 (s, 3H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ148.60, 142.57, 137.54, 129.60, 129.32, 126.42, 126.38, 126.35, 126.33, 124.86, 124.15, 123.30, 122.70, 97.72, 12.31, 12.00. It can be seen that the structure of the obtained product is the target product 4e.

Embodiment 24

Phenyl 4-hydrazinopyrimidine (1f, 0.5mmol), acetylacetone (2a, 0.5mmol), diethyl 2- _{bromomalonate} ( ₃ , 0.5mmol), ^nBu4NBF4 (0.5mmol) and 6mL acetonitrile were placed in a non-separation electrolytic cell, with platinum electrodes (Pt) as anode and cathode, and electrolyzed at room temperature and 10mA constant current for 12h. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/petroleum ether) to obtain the target product 4f (yield: 60%).

The results of nuclear magnetic resonance showed that ¹ HNMR (500 MHz, CDCl ₃ ) δ9.21 (s, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.33 (s, 1H), 2.63 (s, 3H), 2.30 (s, 3H). ¹³ CNMR (126 MHz, CDCl ₃ ) δ149.74, 149.42, 141.15, 141.08, 141.07, 139.75, 138.02, 99.90, 13.47, 12.55. It can be seen that the structure of the obtained product is the target product 4f.

Embodiment 25

Cyclohexylhydrazine (1 g, 0.5 mmol), acetylacetone (2a, 0.5 mmol), diethyl 2-bromomalonate ( ₃ , 0.5 mmol), ^nBu4NBF4 (0.5 mmol) and 6 mL of _acetonitrile were placed in a non-separation electrolytic cell, with platinum electrodes (Pt) as anode and cathode, and electrolyzed at room temperature and 10 mA constant current for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/petroleum ether) to obtain 4 g of the target product (yield: 80%).

The results of nuclear magnetic resonance showed that ¹ HNMR (500MHz, CDCl ₃ )δ3.88(d, J＝6.0Hz,1H),2.21(d, J＝9.0Hz,6H),1.88(d, J＝7.5Hz,6H),1.71(d, J＝7.5Hz,1H),1.30(m,3H). ¹³ CNMR (126MHz, CDCl ₃ )δ145.28,135.80,93.60,58.50,32.63,25.74,25.15,12.32,10.21. It can be seen that the structure of the obtained product is the target product 4g.

Embodiment 26

Phenylhydrazine (1a, 0.5mmol), 3,5-heptanedione (2b, 0.5mmol), diethyl 2- _{bromomalonate} ( ₃ , 0.5mmol), ^nBu4NBF4 (0.5mmol) and 6mL acetonitrile were placed in a non-separation electrolytic cell, with platinum electrodes (Pt) as anode and cathode, and electrolyzed at room temperature and 10mA constant current for 12h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/petroleum ether) to obtain the target product 4h (yield: 68%).

The results of nuclear magnetic resonance showed that ¹ HNMR (500MHz, CDCl ₃ )δ7.40-7.35 (m, 2H), 7.30 (d, J＝7.5Hz, 3H), 2.60 (d, J＝7.5Hz, 4H), 1.21 (t, J＝7.5Hz, 3H), 1.03 (t, J＝7.5Hz, 3H). ¹³ CNMR (126MHz, CDCl ₃ )δ152.46, 142.94, 129.18, 128.10, 125.31, 94.35, 20.40, 18.66, 12.97, 12.87. It can be seen that the structure of the obtained product is the target product 4h.

Example 27 Mechanism Control Experiment

In order to further verify the reaction mechanism of the bromination reaction, the inventors used 1-phenyl-3,5-dimethylpyrazole 5 as the reaction raw material and investigated the bromination reaction under the optimized conditions. Then, under the optimized reaction conditions, 2 equivalents of free radical scavenger (BHT, 2,6-di-tert-butyl-p-cresol) were added to the reaction system to investigate the free radicals present in the reaction system.

1-Phenyl _- 3,5-dimethylpyrazole 5, diethyl 2-bromomalonate (3, 0.5 mmol), ^nBu4NBF4 ( _0.5 mmol) and 6 mL of acetonitrile were placed in a non-separation electrolytic cell, with platinum electrodes (Pt) as anode and cathode, and electrolysis was carried out at a constant current of 10 mA for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/petroleum ether) to obtain the target product 4a (yield: 92%).

The results of nuclear magnetic resonance showed that ¹ HNMR (500 MHz, CDCl ₃ ) δ7.43 (t, J=7.5 Hz, 2H), 7.35 (d, J=7.5 Hz, 4H), 2.27 (s, 7H). ¹³ CNMR (126 MHz, CDCl ₃ ) δ147.52, 139.93, 137.45, 129.12, 127.76, 124.65, 96.34, 12.32, 11.72. It can be seen that the structure of the obtained product is the target product 4a.

Phenylhydrazine (1a, 0.5mmol), acetylacetone (2a, 0.5mmol), diethyl 2-bromomalonate ( ₃ , 0.5mmol), ^nBu4NBF4 (0.5mmol), BHT (1.0mmol) and _6mL acetonitrile were placed in a non-separation electrolytic cell, with platinum electrodes (Pt) as anode and cathode, and electrolyzed at a constant current of 10mA for 12h. After the reaction, the reaction stock solution was analyzed by GC-MS, and the results showed that compound 6 (MS: 378.2) was present in the reaction solution. Then, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/petroleum ether) to obtain the target product 4a (yield: 84%).

The results of nuclear magnetic resonance showed that ¹ HNMR (500 MHz, CDCl ₃ ) δ7.43 (t, J=7.5 Hz, 2H), 7.33 (d, J=7.5 Hz, 3H), 2.26 (s, 6H). ¹³ CNMR (126 MHz, CDCl ₃ ) δ147.51, 139.92, 137.44, 129.11, 127.75, 124.64, 96.33, 12.31, 11.71. It can be seen that the structure of the obtained product is the target product 4a.

It can be seen from the above experimental results that 1-phenyl-3,5-dimethylpyrazole 5 is an important intermediate in the bromination reaction process, and there is a diethyl malonate free radical in the reaction system (which combines with the BHT free radical scavenger to generate compound 6). Therefore, the possible reaction mechanism of the present invention is: first, phenylhydrazine (1a) and acetylacetone (2a) undergo a cyclization reaction to obtain the 1-phenyl-3,5-dimethylpyrazole (5) intermediate. And 2-bromomalonate (3) is reduced at the cathode to generate a radical anion, and then Br- and diethyl malonate free radicals are released. On the anode surface, 1 ^- phenyl-3,5-dimethylpyrazole 5 is anodically oxidized to obtain a radical cation, and reacts with ^Br- to obtain a radical intermediate, and then anodically oxidized and deprotonated to obtain the target product 4a.

In summary, the preparation method of the present invention uses hydrazine, 1,3-propanedione and diethyl 2-bromomalonate as raw materials, and first obtains pyrazole compounds through cyclization reaction under electrolytic conditions, and then generates 4-bromopyrazole compounds through electrocatalytic bromination; the reaction is a multi-component "one-pot" reaction, and three new chemical bonds are formed simultaneously in one step reaction. Compared with the step-by-step reaction, the multi-component reaction has higher efficiency and avoids the complicated post-processing process. And using diethyl 2-bromomalonate as the bromination reagent, compared with the method of using sodium bromide as the bromine source, diethyl 2-bromomalonate has a higher oxidation state and is difficult to be anodic oxidized, thereby avoiding the peroxidation effect and reducing the amount of bromination reagent. Only one equivalent of bromination reagent can efficiently obtain 4-bromopyrazole compounds. And the substrate of the present invention has wide applicability, mild reaction conditions, green and efficient, which is conducive to industrial production.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims (4)

1. The preparation method of the 4-bromopyrazole compound is characterized by comprising the following steps of: placing a hydrazine compound (1), a1, 3-propanedione compound (2), diethyl 2-bromomalonate (3) and an electrolyte in an organic solvent to obtain a reaction solution, placing two electrodes in the reaction solution for constant current electrolysis, fully reacting, and performing aftertreatment to obtain a 4-bromopyrazole compound (4);

Wherein R ¹ is H, alkyl, aryl, or aromatic heterocycle; r ²、R³ is alkyl or aryl;

Wherein the molar ratio of the hydrazine compound to the 1, 3-propanedione compound to the diethyl 2-bromomalonate is as follows: 1-3:1:1-3;

the reaction temperature is 25-50 ℃; the reaction time is 10-24 hours;

The constant current intensity is 5-20 mA;

the electrode is one or two of a platinum sheet, a copper sheet, a nickel sheet and an aluminum sheet;

the electrolyte is one or more of tetrabutylammonium tetrafluoroborate, tetraethylammonium tetrafluoroborate, potassium tetrafluorophosphate, lithium perchlorate, tetrabutylammonium iodide and tetraethylammonium perchlorate;

The organic solvent is one or more of acetonitrile, acetone, ethanol, N-dimethylformamide and dimethyl sulfoxide.

2. The method for producing 4-bromopyrazole according to claim 1, wherein R ¹ is C ₁-C₃ alkyl, C ₁-C₃ alkoxy, halogen or halogen-substituted C ₁-C₃ alkyl.

3. The method for producing 4-bromopyrazole according to claim 1, wherein R ¹ is C ₁-C₃ alkyl, aryl, C ₁-C₃ alkyl-substituted aryl or halogen-substituted aryl;

R ² is halogen, C ₁-C₃ alkyl, halogen substituted C ₁-C₃ alkyl or C ₁-C₃ alkoxy;

R ³ is halogen, alkyl of C ₁-C₃, alkyl of C ₁-C₃ substituted by halogen or alkoxy of C ₁-C₃.

4. The method for producing 4-bromopyrazole compound according to claim 1, wherein the post-treatment comprises the steps of: after the reaction is finished, the reaction solution is decompressed and concentrated to remove the solvent, and the residue is separated by column chromatography to obtain the 4-bromopyrazole compound; the eluting solvent in the column chromatography is ethyl acetate/petroleum ether.