Preparation background of pinacol diborate
In recent years, Suzuki coupling, as an important means to achieve direct connection of carbon-carbon bonds, has been widely used in the synthesis of drugs and liquid crystal materials. Among them, the preparation of organic boronic acid or borate ester compounds as coupling precursors has been extensively studied, and the methods are generally divided into two categories: 1) reaction of Grignard or lithium reagents with boron compounds; 2) use of diboronic acid pinacol The ester is directly coupled to the halide.
The former has limited scope of use due to the incompatibility of some groups with Grignard or lithium reagents. In order to reduce the formation of by-products, ultra-low temperature conditions are often required; in contrast, the latter uses metal palladium for coupling conditions. It is mild and has wide adaptability of functional groups and has attracted widespread attention. At the same time, in order to further reduce the cost of precious metals in coupling reactions, catalytic systems using cheaper and more readily available metal nickel, metal zinc and other catalytic systems have recently been developed. Therefore, pinacol diborate is becoming more and more important in organic synthesis.
At present, there are three main types of synthesis of pinacol diborate: The first one: using pinacolborane as the starting material, prepared by dehydrogenation coupling under the catalysis of transition metal platinum-alumina. Since this method uses precious metal platinum as a catalyst, the cost is high and it is not suitable for large-scale production. The second type: Using boron trichloride, dimethylamine, and pinacol as starting materials, it is prepared through substitution, substitution, coupling, and esterification.
This process can range from tens of grams to hundreds of kilograms. In this method, dimethylamine has a low boiling point, is a dangerous gas above 7°C, and is difficult to operate. It is also listed as a restricted chemical in some countries. Therefore, it is not suitable as a general amplification method. The third type: using boron tribromide, dimethylamine, and pinacol as starting materials, through substitution, coupling, and esterification. The disadvantages of this method are the same as the second one. Therefore, in order to solve the shortcomings in the existing synthesis process, it is particularly urgent to find a zinc borate synthesis route that is versatile, has easy-to-obtain raw materials and can be recycled, is simple to operate, has high yield, and is suitable for scale-up production.
Preparation and application of pinacol diborate
Pinacol diborate is a pharmaceutical intermediate. Examples of its applications are as follows:
Preparation of pinacol diborate ester 1. Synthesize an indole compound.
Comprising the following steps: (1) Stir o-nitrostyrene or its derivatives, pinacol diborate, alkali and lower saturated monohydric alcohol under nitrogen atmosphere; (2) Stir the reaction of step (1) The reaction product is cooled to room temperature, then ethyl acetate is added and mixed thoroughly, filtered, and then washed with ethyl acetate; (3) spin dry the lower saturated monohydric alcohol in the organic phase of the material obtained in step (2), and pass it through a silica gel column , and then use an eluent composed of petroleum ether and ethyl acetate to elute the above-mentioned silica gel column to obtain a purified product, namely the indole compound.
The catalytic synthesis method of the present invention uses cheap pinacol diborate as raw material and friendly low-grade saturated monohydric alcohol as solvent under neutral conditions to obtain indole compounds through simple operations, with low raw material cost. It is cheap and easy to obtain, has high efficiency, good safety, wide expansibility and good industrial application prospects.
Preparation of pinacol diboronate 2. Synthesis of an alkyl boron ester compound.
That is, Fe(acac)3 (acac=acetylacetonate) is used as a one-component catalyst in the presence of metallic magnesium to synthesize alkyl boron through the cross-coupling reaction of chlorinated alkanes and pinacol diborate. ester compound method. The method for synthesizing alkyl boron ester compounds provided by the invention not only avoids the use of sensitive metal organic reagents and multi-component catalysts, but also realizes the bilateral utilization of pinacol diborate and significantly reduces the use of pinacol diborate. The dosage can make the coupling reaction involving cheap and easily available chlorinated alkanes proceed smoothly under mild conditions; compared with those reported in the literature, it has better atom economy, equivalent or higher catalytic efficiency and wider catalytic efficiency. Substrate suitability.
Preparation of pinacol diborate
A method for synthesizing pinacol diborate, using tetrahydropyrrole and boron tribromide that are readily available on the market as raw materials, and in the presence of the acid-binding agent triethylamine, a trisubstituted boron intermediate is obtained, and then Then it reacts with boron tribromide to obtain a bromide boron intermediate, and then the bromide boron intermediate is coupled in the presence of metallic sodium to obtain a tetrahydropyrrole-substituted diboron. Finally, after adding pinacol and reacting, the desired target product diboron acid pin is obtained. That alcohol ester. Among them, tetrahydropyrrole can be recycled directly, and triethylamine hydrobromide can also be recycled after simple neutralization and drying.
The specific method is:
In step one, mix tetrahydropyrrole, triethylamine and the solvent evenly, then cool it to -15~-10°C, and then slowly add the mixture of boron tribromide and the solvent that has been previously cooled to the same temperature. For the reaction solution, control the temperature during the entire addition process at -15 to 0°C, and keep stirring at this temperature for 1 to 3 hours to detect the completion of the reaction. Insoluble solids are filtered off, and the filtrate (product containing trisubstituted boron intermediates) is directly entered into the next step of reaction. The reaction equation is as follows:
Among them: 1) The by-product triethylamine hydrobromide generated by the reaction can be re-freed by adding sodium hydroxide aqueous solution. The triethylamine obtained does not require solvent extraction and is directly separated into layers. After adding n-heptane, it is dehydrated. The toluene solution of triethylamine obtained is reused in this step for recycling. 2) The reaction solvents are n-pentane, n-heptane and toluene, with n-heptane being preferred. 3) The external standard yield of this step reaction is 80-89%.
In step two, cool the reaction filtrate of the first step to -10~0°C, start slowly introducing boron tribromide, control the temperature during the entire addition process at -10~0°C, and maintain this temperature for 2 to 5 seconds hours, the detection reaction is completed. Control the temperature of the reaction solution below 50°C and distill it under reduced pressure until more than 95% of the light components are removed. After cooling, add toluene and mix evenly. The toluene solution (containing the brominated boron intermediate product) directly enters the next step of the reaction. The reaction equation is as follows:
Among them: 1) The molar equivalent of the trisubstituted boron intermediate product and boron tribromide is 1:0.49-0.52. 2) The reaction solvent is n-pentane, n-heptane and toluene. 3) The reaction yield in this step is 85-91%.
In step three, metal sodium and toluene are added to the reaction kettle, the temperature is raised to 90-110°C, and the metal sodium is first prepared into sodium sand. Then maintain the temperature between 90 and 110°C and slowly drip in the reaction solution prepared in the second step. After the dropwise addition is completed, raise the temperature to reflux and continue the reaction for 5 to 8 hours. At this time, the completion of the reaction is detected. The reaction solution was lowered to room temperature, and an appropriate amount of pinacol was added to quench a small amount of unreacted sodium sand. At this time, the reaction solution (containing the tetrahydropyrrole-substituted diborate product) was filtered out of insoluble inorganic salts and then directly used in the next step of the reaction. The reaction equation is as follows:
Among them: 1) The molar equivalent of boron bromide intermediate and metallic sodium is 1:1.02-1.15. 2) If necessary, the product is purified by distillation. 3) The yield of this step is 70-77%.
In step 4, the above reaction solution is heated to 90-105°C, and a mixture of pinacol and toluene is added dropwise. During the dropwise addition of calcium and magnesium carbonate, tetrahydropyrrole is continuously distilled out and the reaction continues. When all the pinacol is added, continue to maintain the reaction temperature for 3 to 5 hours and the controlled reaction is completed. After the reaction solution cools to room temperature, add saturated ammonium chloride solution to adjust the pH to 6-7, wash with saturated brine, spin the organic layer to dryness, and add a low-polarity solvent to beat to obtain the product. The reaction equation is as follows:
Among them: 1) The molar equivalent of the raw material and pinacol is 1:2.1-2.4. 2) The tetrahydropyrrole produced by the reaction is distilled out during the reaction, and can be recycled directly into the first step after deducting the solvent conversion content. . 3) The low-polarity solvents used for crude pulping are n-heptane and n-hexane, and n-heptane is preferred. 4) When necessary, the product needs to be recrystallized to form better crystal grains. 5) The yield of this step is 78-85%.
7. Wash with saturated brine, spin the organic layer to dryness, add a low polarity solvent and beat to obtain the product. The reaction equation is as follows:
Among them: 1) The molar equivalent of the raw material and pinacol is 1:2.1-2.4. 2) The tetrahydropyrrole produced by the reaction is distilled out during the reaction, and can be recycled directly into the first step after deducting the solvent conversion content. . 3) The low-polarity solvents used for crude pulping are n-heptane and n-hexane, and n-heptane is preferred. 4) When necessary, the product needs to be recrystallized to form better crystal grains. 5) The yield of this step is 78-85%.
