ChemicalBook CAS DataBase List 2,6-Difluoropyridine-3-boronic acid

2,6-Difluoropyridine-3-boronic acid synthesis

6synthesis methods

Product Name:2,6-Difluoropyridine-3-boronic acid
CAS Number:136466-94-9
Molecular formula:C5H4BF2NO2
Molecular Weight:158.9

1513-65-1

121-43-7

136466-94-9

The general procedure for the synthesis of 2,6-difluoropyridine-3-boronic acid from 2,6-difluoropyridine and trimethyl borate was carried out as follows: the synthesis was carried out according to the methodology reported in the literature [S1, S2] with appropriate modifications. First, a solution of lithium diisopropylammonium (LDA) was prepared by slow dropwise addition of a THF (20 mL) solution of diisopropylamine (3.4 mL) to n-butyllithium (1.67 M in n-hexane, 24 mmol, 14 mL) at 20 °C, followed by stirring at 0 °C for 20 min. Next, in another reaction flask, a solution of 2,6-difluoropyridine (20 mmol, 1.8 mL) in THF (20 mL) was stirred at -78 °C and the LDA solution prepared above was added via cannula. After continued stirring at -78 °C for 30 min, a solution of trimethyl borate (24 mmol, 2.5 g, 2.7 mL) in THF (10 mL) was added to the reaction mixture, followed by a slow warming up to room temperature over a period of 1 hour. Upon completion of the reaction, the reaction was quenched with 2 M aqueous sodium hydroxide solution (40 mL). The aqueous layer was separated and the pH was adjusted to 8 with 4 M hydrochloric acid followed by extraction with ethyl acetate (organic layer A). The pH of the aqueous layer was further adjusted to 6.5 with 4M hydrochloric acid, at which time insoluble organic matter was precipitated, and the extraction was repeated three times with ethyl acetate to give organic layer B. The pH of the aqueous layer was again adjusted to 4 with 4M hydrochloric acid, and the extraction was repeated three times with ethyl acetate to give organic layer C. Organic layers B and C were combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product of 2,6-difluoropyridinium-3-boronate in 94% (3.0 g) yield. 94% (3.0 g, 19 mmol). The product could be used directly in the subsequent reaction without further purification.

1513-65-1
341 suppliers
$6.00/5g

121-43-7
384 suppliers
$13.00/25mL

136466-94-9
214 suppliers
$8.00/250mg

Yield:136466-94-9 94%

Reaction Conditions:

Stage #1:2,6-difluoro pyridine with n-butyllithium;lithium diisopropyl amide in tetrahydrofuran;hexane at -78; for 0.5 h;
Stage #2:Trimethyl borate in tetrahydrofuran at 20; for 1 h;

Steps:

2’,6’-Difluoro-2,3’-bipyridine, L2
L2 was synthesized according to literature procedures [S1,S2] with some modifications. In around-bottomed flask, lithium diisopropylamide (LDA) solution was prepared as follows: THF (20mL) solution of diisopropylamine (3.4 mL) was slowly added n-butyl lithium (1.67 M in n-hexane,24 mmol, 14 mL) at 0 C, then was stirred at the same temperature for 20 min. In anotherround-bottomed flask, THF (20 mL) solution of 2,6-difluoropyridine (20 mmol, 1.8 mL) was stirredat -78 C and was added LDA solution prepared above via a cannula. After stirring at -78 C for 30min, the reaction mixture was added THF (10 mL) solution of trimethyl borate (24 mmol, 2.5 g, 2.7mL), then warmed to ambient temperature over 1 h. The reaction was quenched by adding 2Maqueous sodium hydroxide (40 mL). Separated aqueous layer was neutralized (pH 8) by adding 4Mhydrochloric acid and extracted with ethyl acetate (organic layer A). Re-adding 4M hydrochloricacid to the aqueous layer to pH 6.5 afforded insoluble organic materials. Repeated extraction withethyl acetate for three times gave organic layer B. Re-adding 4M hydrochloric acid to the aqueouslayer to pH 4 followed by repeated extraction with ethyl acetate for three times gave organic layer C.The combined organic layer (B and C) was dried over anhydrous sodium sulfate, and concentrated invacuo. 2,6-difluoropyridine-3-boronic acid was obtained in 94% yield (3.0 g, 19 mmol) as theresidue. This compound was used for the next step without further purification.

References:

Takahira, Yusuke;Murotani, Eisuke;Fukuda, Keiko;Vohra, Varun;Murata, Hideyuki [Journal of Fluorine Chemistry,2016,vol. 181,p. 56 - 60] Location in patent:supporting information

FullText

1513-65-1
341 suppliers
$6.00/5g

121-43-7
384 suppliers
$13.00/25mL