Preparation of 2-chloro-4-methylbenzeneboronic acid_Industrial additives

Background and overview^[1]

2-Chloro-4-methylbenzeneboronic acid can be used as a pharmaceutical synthesis intermediate and is often used as a raw material for coupling reactions such as Suzuki. 2-Chloro-4-methylbenzeneboronic acid can be prepared by reacting 2-chloro-4-methyl-1-iodobenzene with n-butyllithium.

Preparation^[1]

Step 1: Preparation of 2-chloro-4-methyl-1-iodobenzene

Add concentrated sulfuric acid (80ml) to the stirring mixture of 2-chloro-4-methylaniline (0.4mol) and distilled water (ml), then briefly heat to 60°C for 1 hour until dissolution is complete . The mixture was allowed to cool to room temperature and then further cooled to approximately 0°C in an ice/salt bath. An aqueous solution of sodium nitrite (28 g, 0.4 mol) in distilled water (140 ml) was added dropwise to the slurry over 15 minutes while maintaining the temperature below 5°C, and then stirred for a further 30 minutes. The reaction mixture was allowed to return to room temperature and a solution of potassium iodide (199 g, 1.2 mol) in distilled water (200 ml) was added dropwise at room temperature. After the addition is complete, the solution is briefly heated to 80°C and then allowed to cool to room temperature again. The reaction mixture was extracted with ethyl acetate (1000mlx3), and the organic phase was washed with 1M aqueous hydrochloric acid solution (500ml) and aqueous sodium thiosulfate solution (2x250ml). The organic phase was dried over anhydrous sodium sulfate, filtered and the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-chloro-4-methyl-1-iodobenzene as an orange solid.

Step 2: Preparation of 2-chloro-4-methylphenylboronic acid

At -75°C, n-butyllithium (1.6M hexane solution, 188ml) was added dropwise to a solution of 2-chloro-4-methyl-1-iodobenzene (0.25mol) in tetrahydrofuran (800ml). 0.3 mol) while maintaining the temperature of the reaction mixture below -70°C. When the addition was complete, the mixture was stirred at -75°C for a further 30 minutes, then trimethylborate (153.7g, 1.48mol) was added dropwise. After the addition was complete, the reaction was stirred at -75°C for 1 hour, then allowed to return to room temperature and stirred for 2 hours, then cooled by an ice bath and acidified with 0.5N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (3x500ml) and the organic fractions were combined, washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-chloro-4-methylphenylboronic acid as a white solid.

Main reference materials

[1][Chinese invention] CN200880124382.1 4-phenylpyran-3,5-dione, 4-phenylthiopyran-3,5-dione and 2-phenyl used as herbicides Cyclohexan-1,3,5-trione