1-Ethynyl-4-fluorobenzene → HCID 90402679, compound

Participants

Reaction Conditions

Reaction Steps

5-bromo-6-chloro-3-iodopyridin-2-yl acetate (14.5 g, 38.5 mmol) was dissolved in THF (50 mL) and cooled to 0° C. TEA (2.5 mL), Copper(I)Iodide (0.514 g, 2.70 mmol), and bistriphenylphosphine palladiumdichloride (0.270 g, 0.385 mmol) were added to the reaction mixture. The mixture was degassed and charged with N2 (3×). Next, 1-ethynyl-4-fluorobenzene (5.55 g, 46.2 mmol) was added drop wise over the course of 1 h at 0° C. The reaction mixture was then allowed to slowly warm to rt and continue to stir for 18 h. LCMS and TLC show the reaction to be incomplete. An additional 2.5 mL of TEA was added. The mixture was then allowed to stir at rt over a long weekend (80 h). At this point, LCMS and TLC show no remaining starting material. The reaction mixture was concentrated to a dry solid. This solid was then taken up in DCM (50 mL) and washed with sat NH4Cl. The aq layer was extracted with DCM (2×20 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated to >15 g of a brown solid. This solid was dissolved in DCM, adsorbed onto Celite and then flashed on silica gel eluting with a 10-100% DCM in hexanes gradient over 15 column volumes to give 5-bromo-6-chloro-3-((4-fluorophenyl)ethynyl)pyridin-2-yl acetate (11.7 g, 31.7 mmol, 82% yield) as a tan solid. LCMS: m/e 369 (M+H)+ LCMS retention time: 3.74 min. (Column: Phenomenex-Luna 50×2.0 mm 3u. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=4 min. Flow Rate=0.8 mL/min.). 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (s, 1H), 7.48 (dd, J=8.7 Hz, 2H), 7.09 (dd, J=8.7 Hz, 2H), 2.39 (s, 3H).

Provenance & Evidence