Background and overview[1]
Aminoboronic acid pinacol ester is used as an intermediate in the synthesis of drugs and organic light-emitting materials (LEDs). Currently, most of the focus is on the application of this type of compound. Synthetic Method Due to the special nature of the amino group itself, the synthetic method is also different at different substitution positions. Compared with the ortho-position and meta-position, there are relatively more studies on p-aminophenylboronic acid pinacol ester. There are fewer reports on the synthesis method of 2-aminophenylboronic acid pinacol ester, and there is only the synthesis of o-aminophenylboronic acid, that is, starting from phenylboronic acid, it reacts with fuming nitric acid in an acetic anhydride solvent to obtain o-nitrobenzeneboronic acid. After separation, it is obtained by hydrogenation reduction with palladium on carbon. The disadvantage of this method is that the o-nitrobenzene boric acid obtained in the first step contains a certain proportion, which requires multiple recrystallizations to remove. At the same time, the product anthranilic acid obtained after reduction has a certain balance with its own dimer, and the purity is difficult to determine.
Preparation[1]
2-Aminophenylboronic acid pinacol ester is prepared as follows:
1) Synthesis of 2-bis(trimethylsilyl)aminobromobenzene (1, ortho):
Under argon protection, in a 3L three-necked flask equipped with magnetic stirring, add 2-aminobromobenzene (172 g, 1.0 mol) and triethylamine (303.6 g, 3.0 mol) into 850 ml of anhydrous THF solvent , start stirring, cool the reaction solution to about 0°C, and then slowly drop 3.0 equivalents of trimethylsilyl chloride (325.9 g, 3 mol). During the dropwise addition, the system temperature rises to 30°C. After the dropping, stir for 10 minutes, and then react at 40-60°C for 1-3 hours. TLC detects that the reaction is complete. The developing solvent is: n-hexane/ethyl acetate = 10:1. At this time, it is the previous trimethylsilyl-protected intermediate. Cool the temperature to -10~0°C, and maintain this temperature to add 1.5 equivalents of commercially available 3M methylmagnesium chloride in tetrahydrofuran solution (500 ml, 1.5 mol), and then add 3.0 equivalents of trimethylsilyl chloride (303.6 g, 3.0 mol) dropwise. React for 2 to 5 hours. TLC detects that the reaction is complete. The developer system is the same as above. The reaction system was sealed and filtered, and the filtrate was distilled under reduced pressure to obtain 243.6 grams of 2-bis(trimethylsilyl)aminobromobenzene 1 product, with a GC content of 96.7% and a yield of 77%. Directly add 720 ml of anhydrous tetrahydrofuran and use it for the next step.
2) Synthesis of 2-bis(trimethylsilyl)aminolithium (2, ortho):
Under argon protection, in a 3L three-necked bottle equipped with magnetic stirring, cool the THF solution obtained in step 1 above to below -70°C, and begin to slowly add 2.5M n-butyllithium hexane solution ( 370 ml, 0.924 mol, 1.2 equivalent), the temperature should not exceed -70°C during the dropwise addition, and the dropwise addition should be completed in 1-1.5 hours. Continue to maintain the temperature and stir for 1 hour. TLC detects that the exchange is complete. The developing solvent is: n-hexane/ethyl acetate: 10:1. The reaction solution is 2 bis(trimethylsilyl)aminophenyllithium (2, ortho), which is directly used in the next step of the reaction.
3) Synthesis of 2-aminobromoboronic acid pinacol ester (3, ortho):
Under argon protection, add trimethyl borate (120 g, 1.16 mol, 1.5 equivalents) and 350 ml anhydrous tetrahydrofuran into a 5L three-necked flask equipped with magnetic stirring, and then cool to below -70°C. Slowly drop the reaction solution in step 2, and control the temperature not to exceed -60°C during the dropwise addition. After the dropwise addition is completed, maintain the reaction at -70~60°C for 2 hours, and detect the completion of the reaction by GC. Detection method: Add a small amount of the reaction solution to tetrahydrofuran containing pinacol, conduct GC analysis after ultrasonic treatment. Slowly add 180 ml of methanol, while the internal temperature gradually rises to room temperature, and continue stirring for 1 hour. After checking that the reaction is complete, add 1.0 equivalent of pinacol (91 g, 0.77 mol) and stir at room temperature for 2 to 3 hours. After the intermediate control reaction was completed, TLC was used for analysis. The developing solvent was n-hexane/ethyl acetate = 5:1. Cool to 0°C, add 10% hydrochloric acid to adjust the pH to 6, separate the liquids, add 350 ml of ethyl acetate to the aqueous layer and extract twice, combine the organic layers, spin dry under vacuum, add 160 ml of n-heptane to the crude product and beat to obtain 87.7 g 2-Aminoboronic acid pinacol ester 3, yield 52%, GC: 98.4%. The product is a light yellow solid, melting point: 66-67°C, HNMR (CDCl3, MHz, ppm): 7.61 (dd, 1H), 7.21 (m, 1H), 6.66 (m, 1H), 6.60 (d, 1H), 4.71(s, 2H), 1.33(s, 12H);
Main reference materials
[1]CN201510010047.0 A method of synthesizing aminophenylboronic acid pinacol ester
