Diisopropylamine → 2-Fluoro-5-(1-morpholinoethyl)pyridin-3-ylboronic acid

Participants

Reaction Conditions

Reaction Steps

A stirred solution of diisopropylamine (2.152 mL, 15.35 mmol) in tetrahydrofuran (20 mL) was treated with n-butyllithium 1.6M in Hexanes (9.60 mL, 15.35 mmol) at −40° C. The yellow solution was stirred at the same temperature for 1 h and then cooled to −78° C. A solution of 4-(1-(6-fluoropyridin-3-yl)ethyl)morpholine (2.69 g, 12.79 mmol) in THF (15 mL) was added via cannula over 20 min. The deep-red mixture was stirred at the same temperature for 1.5 h. Then a solution of triisopropyl borate (4.41 mL, 19.19 mmol) in THF (10 mL) was added slowly into the mixture. The resulting mixture was stirred at the same temperature for 30 min and then the cooling bath was removed. After the reaction mixture had warmed to room temperature, the tan mixture was quenched with 1 N NaOH (aq) (15 mL) and stirred. The separated aqueous layer was removed and the flask was rinsed with 1 N NaOH (aq) (2×20 mL) and the organic layer was extracted with 1 N NaOH (2×10 mL). The aqueous layer was collected and carefully acidified with 5 N HCl until acidic (pH 5 about 6) and the resulting cloudy mixture was extracted with EtOAc (3×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The product remained in the aqueous layer. The aqueous layer was frozen and the water removed by lyophilization. The mixture was diluted with 1:1 MeOH/DCM and placed into a sonicator for 5 min. The mixture was filtered through a fine-fritted funnel and the filtrate was concentrated in vacuo to give 2-fluoro-5-(1-morpholinoethyl)pyridin-3-ylboronic acid (3.120 g, 12.28 mmol, 96% yield) as a yellow solid. 1H NMR (400 MHz, d4-MeOH) δ 8.00 (dd, J=8.22, 2.54 Hz, 1H) 7.88 (d, J=2.35 Hz, 1H) 3.68 (t, J=4.69 Hz, 4H) 3.40-3.54 (m, 1H) 2.56 (d, J=10.76 Hz, 2H) 2.35-2.50 (m, 2H) 1.41 (t, J=6.65 Hz, 3H). m/z (ESI, +ve ion) 255.1 (M+H)+.

Provenance & Evidence