Methane → 3-Amino-5-bromo-4-hydroxybenzonitrile

Participants

Reaction Conditions

Reaction Steps

To a 22-L, 3-neck round-bottom flask fitted with a stirring paddle, a Claisen adapter fitted with a thermocouple and a condenser blanketed with nitrogen, and an addition funnel capped with a septum was added a mixture of 3-bromo-4-hydroxy-5-nitrobenzonitrile (96.9 g, Step A) in methanol (14 L). To this mixture was added iron (III) chloride (9.3 g) and activated charcoal (38 g, Darco 6-60, 100-mesh powder). The mixture was heated to reflux (65° C.) and stirred for 15 min at this temperature. Hydrazine (80 ml) was added to the refluxing mixture dropwise via addition funnel. Once the addition was complete, the mixture was stirred at reflux for 2 h. The mixture was then allowed to cool, filtered through Celite, washing with methanol, and concentrated to a red oil. A mixture of 300 ml of acetic acid and 700 ml of methanol was added and the mixture was concentrated again and then co-concentrated twice with 800 ml of toluene. The residue was purified by flash chromatography on an Isco Companion XL, 1.5 kg column, eluting with 3 column volumes of 30% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 30 to 60% over 6 column volumes, followed by 2 column volumes of 60% EtOAc in hexanes to provide 40 g (55%) of the title compound. Mass spectrum (ESI) 214.9 (M+1).

Provenance & Evidence