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

Participants

Reaction Conditions

Reaction Steps

A solution of diisopropylamine (0.767 mL, 5.43 mmol) in 2 mL of THF at −40° C. was treated with n-butyllithium (3.4 ml of 1.6 M solution in hexanes, 5.43 mmol) and stirred at this temperature for 30 min. The solution was cooled to −78° C. and treated dropwise via cannula with a solution of 4-((6-fluoropyridin-3-yl)methyl)thiomorpholine (922 mg, 4.34 mmol) in THF (2+2 mL) over 10 min. The brown mixture was stirred at −78° C. for 90 min and then treated dropwise via syringe with a solution of triisopropyl borate (1.49 mL, 6.51 mmol) in THF (1 mL). The mixture was stirred at −78° C. for 30 min. The cooling bath was removed, and the reaction mixture was allowed to warm up to RT. The mixture was quenched with 1.0N NaOH (5 mL) and stirred for an additional 30 min. The mixture was transferred to a separatory funnel and extracted with 5 mL of ether. The ether layer was discarded, and the aqueous layer was carefully acidified with 2.5N aqueous HCl until acidic (pH 4 about 5) and the resulting cloudy mixture was diluted with EtOAc (50 mL). The separated aqueous layer was extracted with EtOAc (2×15 mL) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 2-fluoro-5-(thiomorpholinomethyl)pyridin-3-ylboronic acid (790 mg, 3.08 mmol, 71.0% yield) as an off-white crystalline solid. 1H NMR (400 MHz, d4-MeOH) δ 8.11 (1H, d, J=2.5 Hz); 8.00 (1H, dd, J=8.0, 2.5 Hz); 3.75 (2H, s.); 2.91 (4H, m); 2.73 (4H, br. s.). m/z (ESI, +ve ion) 257 (M+H)+.

Provenance & Evidence