4'-Hydroxyacetophenone → 2-(4-Hydroxyphenyl)indole

Participants

Reaction Conditions

Reaction Steps

To 47.2 g of polyphosphoric acid was added 13.62 g (0.10 mol) of 4′-hydroxyacetophenone and 10.0 mL (0.10 mol) of phenylhydrazine at room temperature. The mixture was heated at 150° C. (oil bath temp) for 1 h. After cooling to room temperature an ice-cold H2O (250 mL) was added and the dark brown mixture was stirred overnight. This was then neutralized with 5.0 N NaOH (100 mL) and extracted with EtOAc (1 L×4) which was washed with saturated aqueous NaHCO3 and brine (500 mL each). Organic layers were dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated to ca. 200-300 mL. This was treated with charcoal, filtered and concentrated. The crude 2-(4-hydroxyphenyl)indole 12.02 g (57%) was obtained. The crude phenolic indole (10.7 g; 51 mmol) was treated with 33.32 g (0.10 mol) of Cs2CO3 and 6.7 mL (56 mmol) of benzyl bromide in ca. 250 mL of DMF at room temperature overnight. The mixture was filtered through a pad of diatomaceous earth with thorough EtOAc rinse. The filtrate was taken up in to 1 L of EtOAc and washed with H2O (500 mL×2) and brine (500 mL) which were back-extracted with EtOAc (1 L×3). Combined organic layers were dried over MgSO4, concentrated and purified by PrepLC with 10:90 benzene-hexanes and 10:10:80 benzene-Et2O-hexanes to obtain 5.34 g (27%) of N,O-dibenzylated product and 1.94 g (13%) of the named benzyl ether.

Provenance & Evidence