Acetic Acid → 3-Bromo-5-methylaniline

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A solution of 3-bromo-5-nitrotoluene (21 g, prepared by the method of R. B. Carlin and G. E. Foltz, J. Amer. Chem. Soc., 1956, 78, 1992) in ethanol (250 ml) containing acetic acid (40.8 g) and iron powder (19.0 g) was refluxed with stirring for 3 h. Additional iron powder (9.5 g) was added, and the reaction mixture refluxed a further 3 h, cooled, and added to excess water. The mixture was filtered and the aqueous filtrate extracted with diethyl ether. The organic layer was extracted with 1N hydrochloric acid, the acid extracts basified with sodium hydroxide and the mixture extracted with diethyl ether. The organic extract was dried and evaporated to give 3-bromo-5-methylaniline (15.6 g) which without further purification was dissolved in methanol (200 ml) containing dimethyl acetylene dicarboxylate (11.37 g). The solution was refluxed for 16 hr, evaporated to dryness, and the residue taken up in ether and washed with dilute hydrochloric acid. Evaporation of the ether gave the intermediate enamine (26.1 g) which was added dropwise to stirring diphenyl ether (250 ml) at 250° C. After 15 minutes, the mixture was allowed to cool to room temperature, the crystalline product collected and recrystallised from acetic acid to give a mixture of the 5,7-regioisomers (23 g). This mixture (5 g) was separated by chromatography on silica gel, eluting with dichloromethane/methanol (94:6) to give methyl 7-bromo-5-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.50 g), mp 270°-271° C., a (360 MHz, DMSO-d6) 2.75 (3H, s, CH3), 3.95 (3H, s, OCH3), 6.51 (1H, s, 3-H), 7.24 (1H, d, 6-H) and 7.99 (1H, d, 8-H) (NOE to 6-H only on irradiation of 5-CH3 confirms regiochemistry); and methyl 5-bromo-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.18 g), mp 258°-9° C., δ (360 MHz, DMSO-d6) 2.37 (3H, s, CH3), 3.95 (3H, s, OCH3) 6.58 (1H, s, 2-H), 7.41 (1H, d, 6-H) and 7.72 (1H, d, 8-H) (NOE to both 6-H and 8-H on irradiation of 7-CH3 confirms regiochemistry).

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