Hydrochloric Acid → 2-Fluoro-5-vinylpyridin-3-ylboronic acid

Participants

Reaction Conditions

Reaction Steps

2-Fluoro-5-vinylpyridine (64.8 mg, 0.526 mmol) was dissolved in THF (2.0 mL) and the reaction flask was cooled in a dry ice/acetone bath. Then, n-butyllithium (1.6 M solution in hexanes, 0.40 mL, 0.64 mmol) was added via syringe dropwise, turning the solution red. The reaction was stirred at −78° C. for 45 minutes, and then triisopropyl borate (Aldrich, St. Louis, Mo. 98+%, 0.190 mL, 0.826 mmol) was added, and the reaction was allowed to slowly warm up to room temperature (the dry ice/acetone bath was removed after 80 minutes). The reaction was stirred at room temperature for 45 minutes, and then quenched with water. The layers were separated, and the organic phase was discarded. The aqueous phase was treated with 5N HCl to lower the pH from 9 to 4. Then, the aqueous phase was extracted with 10:1 DCM/MeOH, and the organic extracts were combined and set aside. In a separate flask, 2-fluoro-5-vinylpyridine (4.15 g, 33.7 mmol) was decanted from a solid precipitate, which was washed with THF. The 2-fluoro-5-vinylpyridine was dissolved in THF (120 mL), and the reaction flask was cooled in a dry ice/acetone bath under nitrogen. Then, n-butyllithium solution (1.6 M in hexanes, 25.5 mL, 40.8 mmol) was added via syringe, turning the yellow solution into a deep red color. The reaction was stirred at −78° C. for 50 minutes, and then triisopropyl borate (Aldrich, St. Louis, Mo. 98+%, 11.5 mL, 50.0 mmol) was added via syringe, and the reaction was allowed to warm to room temperature (after 90 minutes, the dry ice/acetone bath was removed). Almost 5 hours after the addition of triisopropyl borate, the reaction was quenched with water (125 ml), slowly at first. The biphasic solution was stirred for 15 minutes, and then the layers were separated. The organic phase extracted one time with saturated sodium bicarbonate. This sodium bicarbonate washing was discarded. The organic phase was extracted two times with 1 N NaOH (60 mL and then 50 mL). These aqueous extractions were combined, treated with concentrated HCl to lower the pH to 4, and extracted with 10:1 DCM/MeOH. These organic extracts did not contain product, so they were discarded, along with these second aqueous extractions. The original aqueous phase (from the initial phase separation after quenching the reaction with water) was treated with 5N HCl to lower the pH to around 3-4. This aqueous phase was extracted with 10:1 DCM/MeOH. These organic extracts were combined with the organic extracts from the first reaction, concentrated, and dried under high vacuum at room temperature to afford 2-fluoro-5-vinylpyridin-3-ylboronic acid (882 mg, 61% purity, 11% yield over 2 steps). MS (ESI pos. ion) m/z 168 (M+H)+.

Provenance & Evidence