Acetic Acid → 1-(4-Benzyloxy-phenyl)-2-pyridin-4-yl-ethanone

Participants

Reaction Steps

An oven-dried, 3-neck, 250 mL round bottom flask equipped with a magnetic stirbar, addition funnel, and internal thermometer was cooled to ambient temperature under a stream of dry nitrogen. The flask was charged with lithium diisopropylamide, 1.8M solution in THF/heptane/ethylbenzene (22.07 mL, 39.7 mmol), diluted with THF (30 mL), and the solution was chilled to 0° C. To this stirred, 0° C. solution was added dropwise via syringe a solution of 4-methylpyridine (3.87 mL, 39.7 mmol) in THF (25 mL). After the addition was complete the reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was then further chilled to −78° C. To this stirred, −78° C. solution was added dropwise via the addition funnel a solution of 4-(benzyloxy)-N-methoxy-N-methylbenzamide (4.9 g, 18.06 mmol) in THF (30 mL). The resulting reaction mixture was stirred at −78° C. for 2 hours. At this point the reaction was quenched with 4.5 equivalents of acetic acid (4.7 mL) added dropwise to the −78° C. reaction mixture. The reaction was then allowed to slowly warm to ambient temperature overnight. Desired product had precipitated from the reaction mixture. Saturated aqueous sodium bicarbonate was added to the reaction mixture. The two layers were filtered to collect the white, insoluble product (3.765 g, 68.7%), then the layers were separated. The aqueous layer was extracted with EtOAc. The combined EtOAc extracts were diluted with CHCl3 to better solubilize the product, then dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow solid. This solid was rinsed with Et2O repeatedly to remove 4-methylpyridine. The pale yellow solid weighed 1.456 g (26.7%, 95% overall). 1H NMR (300 MHz, CDCl3) δ 9.55 (dd, J=4.5, 1.5, 2H), 8.00-7.94 (m, 2H), 7.45-7.31 (m, 5H), 7.19 (d, J=5.9, 2H), 7.05-6.99 (m, 2H), 5.14 (s, 2H), 4.22 (s, 2H). MS (DCI—NH3) m/z=304 (M+H)+.

Provenance & Evidence