A method for green and efficient synthesis of 3',4'-dichloro-5-fluoro-2-nitrobiphenyl

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a Suzuki-Miyaura coupling reaction based on a low-loading palladium catalytic system and using di-tert-butyl phenyl phosphine as a key ligand, which can efficiently prepare substituted biphenyl compounds by using only 0.002% equivalent of palladium catalyst. The method uses 3,4-dichlorobenzene boronic acid and 2-chloro-4-fluoro nitrobenzene as reaction substrates, and uses the synergistic effect of palladium acetate as a transition metal catalyst, di-tert-butyl phenyl phosphine as a ligand and sodium hydroxide as a base to successfully realize Suzuki-Miyaura cross coupling in a green solvent water, and the target is converted into a structure diverse biphenyl compound. The application successfully develops a new process for one-pot synthesis of biphenyl compounds by precisely constructing a palladium catalytic system, which not only has the characteristics of mild reaction conditions and simple operation, but also shows significant technical advantages in economy, substrate universality and process expandability.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to a method for preparing substituted biphenyl compounds using the Suzuki-Miyaura reaction. The method uses water as the sole solvent, and 3,4-dichlorophenylboronic acid and 2-chloro-4-fluoronitrobenzene as reactants, reacting in the presence of a low-loaded palladium catalyst and di-tert-butylphenylphosphine ligand to synthesize the target compound 3′,4′-dichloro-5-fluoro-2-nitrobenzene. Background Technology

[0002] Bixafen is a novel biphenylpyrazole amide fungicide developed by Bayer AG, Germany. It belongs to the succinate dehydrogenase inhibitor (SDHI) class, specifically a respiratory inhibitor. It acts on complex II of the mitochondrial respiratory electron transport chain in pathogens, specifically succinate dehydrogenase, inhibiting mitochondrial function, hindering energy metabolism, suppressing pathogen growth, and ultimately leading to pathogen death. It is mainly used for fungal control in crops such as wheat, barley, oats, corn, potatoes, grapes, peanuts, and soybeans, treating leaf rust and leaf spot diseases. Due to its systemic, broad-spectrum fungicide properties, high efficiency, low toxicity, environmental friendliness, and significant yield-increasing effects, and its effectiveness against methoxyacrylate-resistant strains, it has become a research hotspot for major pesticide companies in recent years. 3′,4′-dichloro-5-fluoro-2-nitrobiphenyl, as an important intermediate in the synthesis of bixafen, has significant research value; its structure is shown below. Currently, the synthesis of 3′,4′-dichloro-5-fluoro-2-nitrobiphenyl using the Suzuki-Miyaura cross-coupling method (SMCC) has significant advantages. It can be carried out under ambient temperature aqueous phase conditions, using water as the sole solvent, which is in line with the concept of green chemistry.

[0003]

[0004] There are currently many reports on the synthesis of 3′,4′-dichloro-5-fluoro-2-nitrobenzene, as detailed below:

[0005] (1) Chinese patent CN116178264A describes a method for synthesizing the target product 3′,4′-dichloro-5-fluoro-2-nitrobenzene by using 3,4-dichlorobromobenzene as a raw material, preparing 3,4-dichlorobenzene magnesium bromide metal compound via Grignard reaction, followed by a metal transfer reaction to obtain zinc chloride product, and finally reacting it with 2-bromo-4-fluoronitrobenzene via Suzuki coupling reaction. The optimized overall yield is 88.6%, and the product purity is 94.8%. The synthesis method is shown below. Since both the Grignard reaction and the Suzuki coupling reaction require nitrogen protection throughout the process, and the Grignard reagent is highly sensitive to water and air, a strict anhydrous and oxygen-free reaction system is required in industrial production. This not only increases equipment investment but also increases the difficulty of operation and control. Improper protection can easily lead to reaction failure and raw material loss.

[0006]

[0007] (2) Chinese patent CN118812366A describes a coupling reaction using 3,4-dichlorophenylboronic acid and 2-chloro-4-fluoronitrobenzene as raw materials, under the assistance of a Pd / C (palladium on carbon) catalyst, ligand 2-bicyclohexylphosphine-2′,6′-diisopropoxybiphenyl (RuPhos), and the action of potassium carbonate as an acid-binding agent, to obtain 3′,4′-dichloro-5-fluoro-2-nitrobenzene with a yield of 95.8% and a purity of 99.1%. The synthesis method is shown below. This reaction requires the use of a special phosphine ligand (such as RuPhos), which is costly and has limited selection. The post-processing solvent consumption is large and requires supporting recovery equipment. The activity of the palladium on carbon catalyst is easily reduced after recovery, and there is still loss of precious metals. It also relies on reflux heating, which has high energy consumption. Overall, it increases the difficulty of process control and production costs, and is not suitable for large-scale factory production.

[0008]

[0009] (3) WO2008122555A1 discloses a method for synthesizing 3′,4′-dichloro-5-fluoro-2-nitrobenzene from 5-fluoro-2-nitrobenzene and 1-bromo-3,4-dichlorobenzene via decarboxylation coupling. The synthesis method is shown below. This reaction requires a dual transition metal catalysis (copper + palladium) combined with a specific ligand (phenanthroline / triphenylphosphine). The catalyst has many components, high ratio requirements, and contains palladium, a precious metal, which increases the cost of raw materials. In addition, the substrate applicability of this reaction is low, only suitable for the coupling of 5-fluoro-2-nitrobenzene and 1-bromo-3,4-dichlorobenzene. It has poor compatibility with benzoates with other substituents and aryl halides, resulting in low process versatility. The purity and yield of the product are limited. The HPLC purity of the crude product is only 72% to 77.5%, requiring subsequent purification steps. The optimal yield is 87%, but the yield easily drops to 76% after industrial scale-up, resulting in low raw material utilization.

[0010]

[0011] (4) Chinese patent CN117321029A describes a method for synthesizing 3′,4′-dichloro-5-fluoro-2-nitrobenzene via a Suzuki-Miyaura cross-coupling reaction using 4-fluoro-2-chloronitrobenzene and 3,4-dichlorophenylboronic acid as raw materials in a composite catalytic system composed of Pd(OAc)2 and P(t-Bu)Cy2 (tert-butyldicyclohexylphosphine). The yield is 74%, with a Pd loading of 0.005 mol%. The synthesis method is shown below. However, this reaction has a narrow substrate applicability, exhibiting good activity only with aryl chlorides containing electron-withdrawing groups, making it difficult to meet the needs of diversified synthesis. Furthermore, the reaction requires stringent temperature and time control, placing high demands on the temperature control precision of the reaction equipment. In addition, the tert-butyldicyclohexylphosphine ligand used in the reaction is flammable and expensive. Although the ligand exhibits certain catalytic activity in laboratory trials, it poses significant safety risks in industrial production, and its high cost further limits the industrial application prospects of this system.

[0012] Summary of the Invention

[0013] This invention provides a Suzuki-Miyaura coupling reaction between 3,4-dichlorophenylboronic acid and 2-chloro-4-fluoronitrobenzene under palladium catalysis and the action of the ligand di-tert-butylphenylphosphine to yield 3′,4′-dichloro-5-fluoro-2-nitrobiphenyl. 3′,4′-dichloro-5-fluoro-2-nitrobiphenyl is an important intermediate in the synthesis of biphenylpyrazole and has significant development potential in medical technology, pesticides, and chemical synthesis.

[0014] The specific plan is as follows:

[0015]

[0016] A low-load palladium-catalyzed Suzuki-Miyaura coupling reaction involving di-tert-butylphenylphosphine was proposed, using 3,4-dichlorophenylboronic acid (Formula 1) and 2,4-chloro-4-fluoronitrobenzene (Formula 2) in the presence of a transition metal catalyst, a phosphine ligand, and a base, to synthesize 3′,4′-dichloro-5-fluoro-2-nitrobenzene (Formula 3) via a Suzuki-Miyaura coupling reaction with a solvent.

[0017] The method of this invention can achieve one-pot production, reducing reaction steps and thus improving product yield; the raw materials used in the synthesis method are obtained through diverse means and have high economic benefits.

[0018] Preferably, the reaction is carried out under the protection of inert nitrogen gas, which has a good protective effect.

[0019] Preferably, the reaction occurs in the presence of a transition metal catalyst, a phosphine ligand, and a solvent.

[0020] Preferably, the transition metal catalyst is palladium acetate, which has high catalytic activity.

[0021] Preferably, the phosphine ligand is di-tert-butylphenylphosphine.

[0022] Preferably, the alkali is sodium hydroxide.

[0023] Preferably, the solvent is safe and environmentally friendly water.

[0024] Preferably, the molar ratio of 3,4-dichlorophenylboronic acid (Formula 1), 2-chloro-4-fluoronitrobenzene (Formula 2), phosphorus ligand, and transition metal catalyst in the reaction is: 1.0–2.0: 1.0–2.0: 0.005%–0.015%: 0.0001%–0.005%.

[0025] In the presence of transition metal catalysts palladium acetate, alkali sodium hydroxide, and phosphine ligand di-tert-butylphenylphosphine, 3,4-dichlorophenylboronic acid and 2-chloro-4-fluoronitrobenzene undergo a Suzuki-Miyaura coupling reaction to finally produce 3′,4′-dichloro-5-fluoro-2-nitrobenzene.

[0026] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0027] (1) This invention uses water as the only reaction solvent. Compared with toluene, tetrahydrofuran, DMF and DMA used in traditional processes, it is more environmentally friendly, has strong sustainability, greatly reduces the use of organic solvents and reduces waste liquid treatment costs.

[0028] (2) The present invention uses a composite catalytic system of palladium acetate and di-tert-butylphenylphosphine. The amount of palladium acetate used is only 0.002 mol%, while the ligand di-tert-butylphenylphosphine is inexpensive (about 1 / 10 of the price of P(t-Bu)Cy2 ligand), which greatly reduces the cost of catalyst and has a better catalytic effect. The yield of 3′,4′-dichloro-5-fluoro-2-nitrobiphenyl produced by the reaction reaches 95%.

[0029] (3) The starting materials 3,4-dichlorophenylboronic acid and 2-chloro-4-fluoronitrobenzene used in this invention are both commercially available chemicals that are inexpensive, have stable sources, and do not require complex pretreatment.

[0030] (4) The present invention adopts a one-pot synthesis method, which reduces the loss of raw materials and saves reaction time due to fewer reaction steps, thereby improving product yield and reaction efficiency. Moreover, the reaction only requires heating at 120°C, eliminating the need for high-temperature and high-pressure equipment. Conventional microwave reaction flasks can meet the requirements, resulting in low equipment requirements and high safety.

[0031] Instruction manual illustrations

[0032] The attached figures show the proton and carbon NMR spectra of the products from each embodiment. The figure numbers correspond to the embodiment numbers. A is the proton NMR spectrum, and B is the carbon NMR spectrum. Figure 1A The above is the proton NMR spectrum of the product obtained in Example 1. Figure 1B The image shows the carbon NMR spectrum of the product obtained in Example 1. Specific Implementation

[0033] To facilitate understanding by those skilled in the art, the concept of the present invention will be further explained below with reference to embodiments. The specific descriptions of the following embodiments are not intended to limit the present invention, but are merely for the convenience of those skilled in the art to understand the technical solution. All raw materials mentioned in the specification were purchased from the market or synthesized through simple methods. Other pharmaceuticals were purchased from Amex, Bidex, Sigma-Aldrich, Acros, Innochem, Energy Chemical, TCI China, Alfa Aesar, or J&K. The nuclear magnetic resonance spectrometer was a Bruker 400M.

[0034] Example 1

[0035] 3,4-Dichlorophenylboronic acid (190.8 mg, 1.0 mmol), 2-chloro-4-fluoronitrobenzene (175.5 mg, 1.0 mmol), and NaOH (39.9 mg, 1.0 equivalent) were added to a 10 mL dry microwave tube fitted with a stir bar (10 × 5 mm), the tube was sealed with a diaphragm cap, and the tube was purged with a nitrogen atmosphere. Then, 10 μL of Pd(OAc)₂ and P( t Bu)2Ph solution (in 0.002M dichloromethane) (0.002 mol%). Finally, 1.0 mL of water was added using a syringe. The reaction mixture was stirred in an oil bath at 120 °C (500 rpm) for 24 hours. The resulting solution was then cooled to room temperature, and the cap was opened to expose the solution to air. The reaction mixture was subjected to column chromatography in silica gel (200-300 mesh), and washed with 3 × 5 mL of ethyl acetate to obtain a solution. The solvent and volatile substances were removed by rotary evaporation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether) to give a yellow solid (286.0 mg, 95% yield). The 1H and 1C NMR spectra of the product were as follows: Figure 1A and Figure 1B The spectral data is as follows: 1H NMR(400MHz,CDCl3)δ8.02(dd,J=9.0,5.0Hz,1H),7.51(d,J=8.2Hz,1H),7.41(d,J=2.1Hz,1H),7.22(ddd,J=8.9,7.2,2.7Hz,1H),7.11(ddd,J=11.4,8.4,2.4Hz,2H)ppm. 13 C{ 1 H}NMR(101MHz,CDCl3)δ165.5,162.88,144.8,137.5,137.4,133.3,133.1,130.8,129.77,127.6,127.5,127.2,119.1,118.9,116.22,115.99ppm. 19 F NMR(376MHz,CDCl3)δ-103.42ppm。

Claims

1. A low-load palladium-catalyzed Suzuki-Miyaura coupling reaction for the synthesis of 3′,4′-dichloro-5-fluoro-2-nitrobenzene, characterized in that: 3′,4′-dichloro-5-fluoro-2-nitrobenzene (Formula 3) was synthesized by a Suzuki-Miyaura coupling reaction using 3,4-dichlorophenylboronic acid (Formula 1) and 2-chloro-4-fluoronitrobenzene (Formula 2) in the presence of a transition metal catalyst, phosphine ligand, and base, mixed with a solvent.

2. The synthesis method according to claim 1, characterized in that, The reaction was carried out in a catalytic system of palladium catalyst and phosphine ligand, with the two catalysts prepared into a composite catalytic solution using dichloromethane as a solvent.

3. The synthesis method according to claim 1, characterized in that, The alkali is sodium hydroxide, potassium hydroxide, potassium carbonate, triethylamine, pyridine, or imidazole.

4. The synthesis method according to claim 2, characterized in that, The palladium catalyst is palladium trifluoroacetate, palladium acetate, palladium chloride, palladium on carbon, tris(dibenzylideneacetone)dipalladium, or tetra(triphenylphosphine)palladium.

5. The synthesis method according to claim 1, characterized in that, The reaction was carried out under the protection of the inert gas nitrogen.

6. The synthesis method according to claim 1, characterized in that, The solvent is water.

7. The synthesis method according to claim 1, characterized in that, The phosphine ligands are 1,1′-binaphthyl-2,2′-bis(diphenylphosphine), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl, di-tert-butylphenylphosphine, 1,1′-bis(diphenylphosphine)ferrocene, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, or 1,2-bis(diphenylphosphine)ethane.

8. The synthesis method according to claim 1, characterized in that, The reaction temperature is 60–120°C.

9. The synthesis method according to claim 1, characterized in that, The molar ratio of 3,4-dichlorophenylboronic acid (Formula 1), 2-chloro-4-fluoronitrobenzene (Formula 2), phosphorus ligand, and transition metal catalyst in the reaction is: 1.0～1.5：1.0～2.0：0.005％～0.015％：0.0001％～0.002％。

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