2-Phenylbutyric Acid → 1-(4-Hydroxyphenyl)-2-phenylbutan-1-one

Participants

Reaction Conditions

Reaction Steps

A 5.0 L round bottom flask was charged with 164.2 (1.00 mol) (±)-2-phenylbutyric acid (III) and 110.3 g (1.02 mol) anisole and anhydrous toluene (575 mL) and stirred until dissolved. The resulting solution was cooled to 10° C. and 367.5 g (1.75 mol) TFAA added such that the temperature did not rise above 15° C. The solution was heated to 35° C. for 1 h then at 40° C. for 72 h. The solution was cooled to 20° C. and toluene (1300 mL) added followed by 2N NaOH (1.80 mol) with external cooling and vigorous stirring at a rate such that the reaction temperature did not rise above 35° C. The mixture was stirred for 1 h and the pH then adjusted to 10 by addition of 2N NaOH. The aqueous layer was removed and the upper organic layer was washed with H2O (900 mL). The aqueous layer was removed and the toluene layer concentrated to ˜1000 mL via atmospheric distillation. This solution was then quickly added to a stirred mixture of 266.7 g AlCl3 (2.00 mol) and anhydrous toluene (900 mL) at 70° C. The solution was stirred at 70° C. for 1 h, cooled to 15° C., and then added to water (1000 mL, 15° C.) with cooling such that the temperature did not exceed 40° C. After complete addition and cooling to 25° C., EtOAc (900 mL) was added and then stirred for 5 minutes. The lower aqueous layer was removed and the organic layer washed with water (1000 mL). The organic layer was concentrated under reduced pressure (˜60° C.) to ˜1000 mL. The solution was then cooled to 50° C. and hexanes (660 mL) added while maintaining an internal temperature of >50° C. The solution was then cooled slowly to 10° C. during which time crystallization occurred. The mixture was stirred for an additional 30 minutes and filtered through a medium glass fritted funnel and the filter cake washed with cold hexanes (330 mL). The material was dried to constant weight in a vacuum oven at 40° C. to yield 183.1 g (76%) of 8 as a cream solid; mp 127-129° C.; 1HNMR (400 MHz, DMSO-d6): δ 0.80 (t, J=7.3 Hz, 3H), 1.69 (h, J=7.2 Hz, 1H), 2.04 (h, J=7.2 Hz, 1H), 4.62 (t, J=7.2 Hz, 1H), 6.79 (d, J=8.7 Hz, 2H), 7.15-7.33 (m, 5H), 7.91 (d, J=8.7 Hz, 2H), 10.32 (s, 1H).

Provenance & Evidence