Iodine → 1,1-Dimethylethyl N-(4-fluoro-3-iodo-2-pyridinyl)carbamate

Participants

Reaction Conditions

Reaction Steps

An oven-dried 3-neck round bottom flask equipped with an overhead stirrer, temperature probe, and addition funnel was charged with tert-butyl (4-fluoropyridin-2-yl)carbamate (Int-26, 31.8 g, 150 mmol), TMEDA (56.6 mL, 375 mmol) and THF (200 mL). The solution was cooled to −78° C. and a solution of n-butyllithium (2.50 M in hexane, 150 mL, 375 mmol) was added dropwise such that the reaction mixture temperature remained below −70° C. Upon completion of addition, the reaction mixture was stirred at −78° C. for 1 h, and a solution of I2 (95.2 g, 375 mmol) in THF (160 mL) was added via addition funnel. The addition was again controlled to keep the reaction mixture temperature below −70° C., and the resulting mixture was stirred at −78° C. for 1 h. A solution of NaHSO3 (61 g, 580 mmol) in water (200 mL) was added to the reaction mixture as it warmed to room temperature. Ethyl acetate was added and the biphasic mixture was stirred at room temperature for 1 h. Water (500 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (3×400 mL); the organic phases were combined, dried over magnesium sulfate, filtered and concentrated to give an off-white solid. This solid was suspended in methylene chloride (50 mL) and the solid was isolated by suction filtration and washed with a minimum of methylene chloride. The filtrate was concentrated and filtered to give a second crop of product. The solids were combined and dried under vacuum to give tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate as a white solid (45.63 g, 86% yield). LC-MS: (FA) ES+ 339. 1H NMR (400 MHz, d6-DMSO) δ ppm 9.47 (s, 1H), 8.32 (dd, J=8.9, 5.5 Hz, 1H), 7.18 (dd, J=7.2, 5.5 Hz, 1H), 1.44 (s, 9H).

Provenance & Evidence