Benzimidazole is an important nitrogen heterocyclic compound, which has a wide range of biological activities and pharmaceutical applications. In organic synthesis, the synthetic methods of Benzimidazole mainly include the following:
1. Diazo method:
The diazonium method is one of the traditional methods for the preparation of Benzimidazole. As shown in the figure below, first react nitrobenzene with aldehydes or ketones to generate acyl-containing diazo compounds, and then use copper catalysts for Kanaiji coupling reactions to generate Benzimidazole.
The preparation of Benzimidazole by the diazonium method is cumbersome, has high requirements for solvents, and the reaction conditions are relatively harsh, so it is generally not suitable for industrial production and large-scale synthesis.
The following are the experimental steps of the diazonium synthesis of Benzimidazole:
Step 1: Preparation of nitrite salt of aniline:
Take an appropriate amount of aniline (1 mmol) and add it to 10 mL of glacial acetic acid and 5 mL of water, then slowly add sodium nitrite (1 mmol) to the solution. After stirring for 5 min, place it in a water bath at 0 °C to control the temperature. During the reaction, the reactants should be kept below 0°C. Controlling the temperature of the reactants is critical because nitrite is unstable and easily decomposes. After the reaction reaches a satisfactory level, the nitrite of aniline should be used in the next reaction immediately.
Step 2: Preparation of Benzene-1,2-diazonium salt:
Benzene-1,2-dione (1 mmol) was dissolved in a solution of sodium hydroxide (1 mmol). Then, add nitrite prepared with aniline and react at 0°C for 2-3 hours until the reaction is complete. During the reaction, the temperature should be controlled below 0°C. After the reaction, the resulting product forms a solid whose structure can be determined spectroscopically.
Step 3: Preparation of Benzimidazole:
Take benzene-1,2-diazonium salt (1 mmol), add diethyl thioacetate (2 mmol), stir, and react at 0°C for 2-3 hours until the reaction is complete. After the reaction was completed, the reaction solution was added dropwise into cold water to form a precipitate. After treatment with dilute acid, the product was extracted with chloroform and the precipitate was dried over Na2SO4. The structure of the obtained product can be analyzed by NMR spectroscopy.
2. Organic solvent method:
The organic solvent method is an economical and convenient method for the synthesis of Benzimidazole. First, phthalic acid and aminophenol are condensed by heat to generate 1,2-phenylenediamine (ie o-phenylenediamine), and then reacted by heating in an organic solvent to obtain Benzimidazole. The method does not need too many catalysts and reaction conditions, and has simple operation and high yield.
step:
(1) Crush 2-aminobenzonezimidazole:
Add 2-aminobenzonezimidazole into the ball mill, and perform ball milling together with the ball milling body and the ball milling medium until it is uniformly pulverized to obtain micron-sized powder. The purpose of crushing is to increase the specific surface area of 2-aminobenzonezimidazole, which is beneficial to the subsequent reaction.
(2) Acylation reaction:
Add the pulverized 2-aminobenzonezimidazole and carboxylic acid or anhydride reagents into the reaction kettle in a certain proportion, pass in an inert gas (such as nitrogen), and start the acylation reaction at a certain temperature. The specific reaction conditions vary with different reagents and solvents. Generally, the reaction temperature is between 70-120° C., and the reaction time is 4-24 hours.
(3) Alkaline boost:
After the reaction, add a certain amount of alkali (such as sodium sulfate, sodium hydroxide, etc.) to promote the completion of the reaction. The amount of base added is generally 1-2 times the mass of the carboxylic acid or anhydride reagent, and the reaction time is 10-30 minutes.
(4) Separation and purification:
The reaction mixture was poured into a separating funnel, rinsed with water and other solvents to obtain a milky white intermediate product. The intermediate product was transferred to a rotary evaporator, and the solvent was removed by controlling the temperature and vacuum to obtain a preliminary purified product. Finally, the product can be dried in a desiccator to obtain the Benzimidazole product.
Generally speaking, the process of preparing Benzimidazole based on the organic solvent method is relatively simple, but attention should be paid to the selection of reaction conditions and the purification of intermediate products during the reaction. Through repeated testing and optimization, high-purity Benzimidazole can be obtained.
3. Zinc chloride method:
The zinc chloride method is also an important method for the preparation of Benzimidazole. By reacting halobenzene with urea, 2-halophenylurea is generated, and then undergoing a substitution reaction with a zinc chloride catalyst to generate Benzimidazole. Zinc chloride catalyst plays an important role in this reaction, which can increase the reaction rate and yield.
The steps of zinc chloride method are as follows:
3.1. Pretreatment: Collect the required raw materials and reagents. The main raw materials for the synthesis of Benzimidazole are 1,2-phenylenediamine and acetyl substances. In addition, reagents such as sodium carbonate, zinc chloride, and ethanol are required.
3.2. Prepare reactants: first dissolve phenylenediamine in 10 mL of ethanol and stir until completely dissolved. Then 37% HCl was added thereto and kept stirring. Add enough sodium carbonate to adjust the pH of the reaction system to about 7-8, and then add ethanol.
3.3. Add zinc chloride: Dissolve zinc chloride in an appropriate amount of ethanol, then slowly add to the reactant while keeping stirring. The temperature of the reaction mass was kept not to exceed 30°C after the addition.
3.4. Reaction: Stir the reactant at room temperature for 3-6 hours until the product is formed. During the reaction, a small amount of hydrogen chloride may be generated, which needs to be removed in time.
3.5. Recovering the product: after the reaction is completed, the reaction solution is filtered through filter paper, and a solid product is obtained after filtration. The product was redissolved with 10 mL of ethanol, and decolorized by activated carbon to obtain a pure product.
3.6. Product testing: testing the purity, structure and physical properties of the product, such as measuring its melting point, spectrum and other properties, to determine whether the product meets the requirements. In actual operation, it is necessary to optimize the reaction conditions, including reaction temperature, reaction time, reagent amount and other factors, in order to achieve better reaction effect and product yield.
In the Benzimidazole zinc chloride method, zinc chloride acts as a catalyst to help the condensation reaction of aniline and acetyl compounds. The benzimidazole produced by the method has high fineness, controllability and high efficiency, and is one of the important synthesis methods of benzimidazole.
4. Metal catalysis method:
The metal-catalyzed method is one of the emerging methods for the preparation of Benzimidazole, and the commonly used metal catalysts include palladium, copper, iron and the like. Among them, palladium catalyst is widely used in the preparation of Benzimidazole. The specific method is that reactants such as p-phenylenediamine and aromatic acylformic acid are added into the reaction system, and the Benzimidazole is generated through the oxidation reaction of the palladium catalyst.
4.1. Nickel catalytic method:
The synthesis of Benzimidazole using nickel catalyst is realized by the C-N cross-coupling reaction of aromatic amines through carbonyl intermediates. The following are the specific synthesis steps:
Step 1: Under basic conditions, aromatic amine hydroxides are prepared and converted into aromatic amine donors. In the reaction, it is necessary to use a metal reducing agent (such as Zn) to reduce the nitrogen atom of the aromatic amine.
Step 2: The donor and carbene (CHCl3/TMF/Ni) were added to the reaction, and the catalyst was reduced to Ni(0) by Ni(CO)4 to form a carbonyl intermediate, which was formed by addition reaction with carbene.
Step 3: Under the condition of heating and stirring, the intermediate forms the corresponding compound of Benzimidazole through internal proton transfer, and the product can be purified by water extraction and column chromatography.
4.2. Palladium catalyzed method:
Using palladium catalyst to synthesize Benzimidazole is a method with high selectivity, high yield and fast reaction speed. The steps of this method are as follows:
Step 1: Condensation reaction of aniline and aromatic acid (or functionalized aryl halide) under basic conditions to generate aromatic acid benzamide.
Step 2: adding a palladium catalyst and an alkaline substance to make the aromatic acid benzamide undergo a dehydration reaction to form an aromatic amide, and then react with an aldehyde or a ketone to generate an intermediate containing N-C and C-C bonds.
Step 3: The intermediate is then catalytically reduced by a palladium catalyst to form the corresponding product of Benzimidazole.
In conclusion, the metal-catalyzed synthesis of Benzimidazole has many advantages, such as good specificity, high efficiency, economy, and easy operation. This article describes the two most common methods for the synthesis of Benzimidazole: nickel-catalyzed and palladium-catalyzed. Especially the palladium catalysis method has been widely used in the industrial production of Benzimidazole because of its advantages of high selectivity, fast reaction speed and simple operation.
In addition, there are some other synthetic methods, such as the condensation reaction of naphthalene and urea to generate Benzimidazole and the like. Generally speaking, there are various synthetic methods of Benzimidazole, and a suitable method can be selected according to different reaction conditions and reaction systems.