Synthesis method of 4-hydroxyphenylboronic acid_Kain Industrial Additive

Background and overview^[1]

4-Hydroxyphenylboronic acid is an organic acid and can be used as an intermediate in organic synthesis.

^{Synthesis method[1-2]}

Method 1: Synthesis of p-hydroxyphenylboronic acid: Under nitrogen protection, add 1.5 kg of 4-methoxyphenylboronic acid, 20 liters of toluene and 1.17 kg of acetyl chloride into a 30L glass reactor. After the addition is completed, cool down the reaction solution. to -10~0°C and stir for 1 hour. Begin to add 267 grams of anhydrous aluminum trichloride in batches. After the addition is completed, raise the temperature to 80°C and keep stirring until TLC shows that the raw material reaction is complete. This process takes about 3 to 5 hours. During this process, the solids in the reaction mixture gradually dissolved, and then solids gradually precipitated. Add 2M sodium hydroxide aqueous solution to quench, and adjust the pH to 11 to 12. At this point the organic layer was separated and discarded. Add 6M hydrochloric acid aqueous solution to the aqueous layer to adjust pH = 2, extract twice with 15 liters of ethyl acetate, combine the organic layers, wash with saturated brine, spin dry the organic layer, add acetone/n-heptane and beat to obtain white crystalline solid p-hydroxyphenylboronic acid 1.01 kg, yield 73%, HPLC content: 99.1%.

Method 2: Preparation of 4-hydroxyphenylboronic acid:

In a 100ml three-necked bottle, add 17g (0.1mol) 4-bromophenol, 16.5g (0.11mol) dimethyl tert-butyl chlorosilane, 30ml DMF, 20ml triethylamine and 0.1gDMAP. React at room temperature for 24 hours. After the reaction is completed, add equal volumes of water and petroleum ether, let stand and separate, remove the aqueous phase, wash with water until neutral, and rotary evaporate to remove the solvent to obtain a colorless oily liquid. In a 250ml three-necked bottle, add 2.6g (0.11mol) Mg chips, a small particle of crystalline iodine and 50ml tetrahydrofuran in sequence. Mix 28.70g (0.1mol) 1-bromo-4-[(1,1-dimethylethyl)dimethylsiloxy]-benzene and 20ml tetrahydrofuran for later use. Add a small amount of the above solution dropwise to initiate the Grignard reaction (if it cannot be initiated, heat slightly to initiate the reaction), and then add the remaining solution dropwise while stirring. Control the dropping speed, use an ice water bath to control the temperature, and keep the reaction temperature below 35°C. After the dripping is completed, stir at room temperature for 1 hour. Cool the system to -65°C in an acetone-liquid nitrogen bath, add dropwise a solution of 11.44g (0.11mol) trimethyl borate in 60ml tetrahydrofuran, and control the temperature at -60°C. After the dripping is completed, stir and naturally raise the temperature to -30°C, and acidify with concentrated hydrochloric acid until it becomes acidic (PH=1). Transfer the reaction solution to a separatory funnel, add 100 ml of ethyl acetate, let stand for liquid separation, wash the organic phase with saturated brine until neutral, separate the aqueous phase, transfer the organic phase to a 250 ml three-necked flask, add 28.71g (0.11 mol) tetrabutylammonium fluoride, react at room temperature for 24 hours, and the reaction is completed. Transfer to a separatory funnel, use saturated brine to neutralize, separate the aqueous phase, rotary evaporate the organic phase to remove the solvent, and recrystallize with petroleum ether to obtain a white solid. Yield 68%; 1H-NMR (500MHz, DMSO-d6): 7.58 (d, 2H), 6.95 (d, 2H), 5.35 (s, 1H).