Acetic Acid → 6-Methoxy-3-nitroquinoline

Participants

Reaction Conditions

Reaction Steps

p-Anisidine hydrochloride (35.0 g, 219.4 mmol) was weighed into a dry 300 mL three-necked round-bottomed flask, equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, a solid addition funnel and a thermometer. Glacial acetic acid (150 mL) was added to the solid, with vigorous stirring to maintain a homogeneous suspension. To this suspension was added sodium nitromalonaldehyde monohydrate (12.0 g, 76.4 mmol) and the mixture stirred for 1.0 h at 25° C. A short-path distillation head was placed on the flask and approximately 120 mL of acetic acid/water removed under reduced pressure at 40° C. To the residue (imine 13) was added glacial acetic acid (40 mL) and sulfolane (75 mL). The resulting solution was flushed with argon to :remove air and the flask immersed in an oil bath preheated to 195° C. The mixture was vigorously stirred while acetic acid was removed by distillation. When the temperature reached 184°-185° C. the mixture was stirred for a further 15 min at 185° C. and then poured (while still at ca. 180° C.) onto crushed ice (750 g). The resulting solution was allowed to stand in a refrigerator (overnight) until precipitation was complete. The dark brown solid precipitate was filtered and transferred to a round-bottomed flask (500 mL) containing 2M hydrochloric acid (250 mL). The mixture was heated at reflux for 50-60 min and the boiling; solution filtered through a preheated Buchner funnel to remove an insoluble brown gum. The hot filtrate was cooled to ca. 4° C. and extracted with chloroform (4×50 mL). The combined extracts were dried (MgSO4) and the chloroform removed on a rotatory evaporator to give the crude 3-nitro-6-methoxyquinoline 14 (9.3 g, brown solid).

Provenance & Evidence