Application overview of methylboronic acid
Catalytic asymmetric reduction is an important way to obtain chiral compounds. As the most classic catalyst for reducing carbonyl compounds: MeCBS and borane are combined to prepare chiral alcohol compounds. This method has high enantioselectivity Sex is still widely used today. As one of the most important reagents, the synthesis of methylboronic acid still lacks effective methods. At present, there are two main methods for synthesizing methylboric acid. One is to react borane with carbon monoxide and then hydrolyze it to obtain methylboric acid. In this method, borane is a flammable gas. Carbon monoxide is very toxic and is very dangerous once it leaks. The other is to react with methyl Grignard reagent and a special unstable chloroboron reagent and then hydrolyze tri-tert-butylphosphine tetrafluoroborate to obtain methylboronic acid. The by-product trimethylboron will inevitably be generated, and trimethylboron will be produced. Methyl boron is very reactive in nature and can easily ignite with air, posing safety risks to production. Secondly, methylboric acid is very water-soluble and is not easy to extract in aqueous solution, which wastes a lot of solvent.
Applications of methylboronic acid
Methylboronic acid is the simplest organic boronic acid derivative and an important intermediate in the preparation of many boronic acid derivatives such as (S) or (R)-2-methyl-CBS-oxazoleborane. Has many uses in synthesis. In addition, methylboronic acid and its derivatives also have significant advantages in chromatographic analysis and are often used for the separation of cis and trans isomers. For example, to prepare chiral MeCBS, add chiral diphenylprolin alcohol and 1.1 to 1.5 equivalents of methylboronic acid to an alkane solvent and reflux to separate the water. After the reaction is completed, cool to 30 to 45°C. After filtering, the filtrate is cooled to ? Stir and precipitate at 20~0°C, filter and dry to obtain chiral MeCBS, which is a white solid with good fluidity. This process is simple to operate and the product obtained has high purity, which provides more options for the current market, which is only available in solution form.
Application and preparation of methylboronic acid
1) Synthesis of (trimethylsilyl)methylboronic acid: Under nitrogen protection, add metal magnesium (0.33 mol) and a few small grains of iodine to a reaction flask equipped with a condenser tube and a constant pressure addition funnel, and stir. 30 ml of a mixed solution of trimethylsilylmethane (0.3 mol) dissolved in 250 ml of 2-methyltetrahydrofuran was added dropwise. Heat to above 40°C and slowly add the remaining solution dropwise after the reaction is initiated. The temperature was raised to reflux for 3 hours and then cooled to room temperature. In another reaction bottle, under nitrogen protection, add trimethyl borate (0.35 mol) and 80 ml of 2-methyltetrahydrofuran. After stirring evenly, cool down to -20°C and start slowly adding the Grignard reagent prepared above. 2 – Complete the addition in 3 hours, keep warm and continue the reaction for 2-2.5 hours. When it is confirmed that the reaction no longer changes, raise the temperature to 0°C and add 10% hydrochloric acid to adjust PH=2. The aqueous layer was extracted once more with 2-methyltetrahydrofuran, and the organic layers were combined and used directly in the next step of synthesis;
2) Synthesis of methylboronic acid trimer: Add the organic layer obtained above into a reaction bottle with methyltetrahydrofuran and a reflux water separation device, and add tetra-n-butylammonium fluoride hydrate (0.4 mol) , the system quickly dissolves under stirring at room temperature. After the reaction is completed, the system solvent is evaporated to dryness under normal pressure. Add 120 ml of toluene to the mixture and start to reflux and separate water. When more than the calculated amount of water is separated, and there is no more water, continue to separate. When it comes out, connect the distillation device to distill out the methylboronic acid trimer generated after the reaction.
3) Synthesis of methylboric acid: Add 4.5 grams of water to the methylboronic acid trimer obtained after the above distillation, stir at room temperature for 30 minutes, and a solid will precipitate. After adding n-heptane and beating, filter to obtain 11.2 grams of pure white solid methylboronic acid, with a yield of 62%. The product GC: 98.2%, the melting point is 88-90°C, and the nuclear magnetic structure is consistent.
