Sulfuric Acid → 2-Methyl-5-nitrophenol

Participants

Reaction Conditions

Reaction Steps

2-methyl-5-nitroaniline (40 g) was dissolved in refluxing 10% sulphuric acid (600 ml), cooled to 0° C. whereupon the salt separates out. With continuous stirring, sodium nitrite solid (18 g) was added in small portions. The diazitization was complete when a positive starch/KI test was observed. This diazonium solution was added at once to a vigorously refluxing solution of water (800 ml) and concentrated sulphuric acid (400 ml). Refluxing was continued until all gassing had ceased. A solid had precipitated out and, upon cooling to ambient temperature, was collected and dried to give crude 2-methyl-5-nitrophenol. This crude phenol (36.8 g) in dimethylformamide (200 ml) along with anhydrous K2CO3 (35 g) and 2-bromopropane (50 ml) was stirred and warmed to 60° C. for 12 hours. After cooling, the solvent was removed, the residue treated with water and the product extracted with ether. This ether solution was washed with 2N KOH, water, dried (MgSO4) and evaporated to give 1-(1-methylethoxy)-2-methyl-5-nitrobenzene, bp. 80°-85° C./0.15 mm., 34.5 g. This nitrobenzene (34.5 g) in methanol (250 ml) was reduced on a parr hydrogenator using Raney nickel. After removal of the catalyst and solvent, the product, 3-(1-methylethoxy)-4-methyl-benzenamine, bp. 80°-85° C./0.05 mm., 25 g. was obtained. This amine (10 g) in methylene chloride (50 ml) and crushed ice (50 g) was stirred whilst thiophosgene (6.5 ml) in methylene chloride (25 ml) was added dropwise. The reaction was stirred overnight at ambient temperature. After separating the organic layer, the methylene chloride solution was washed with water, dried and evaporated to leave a pale yellow oil, bp. 80°-85° C./0.04 mm of 5-isothiocyanato-1-(methylethoxy)-2-methylbenzene, 12,4 g. Ethyl 3-amino-4,4,4-trifluoro-2-butenoate (11 g) was added portionwise to a stirred suspension of sodium hydride (2.5 g, 60%) in tetrahydrofuran (50 ml) at 15° C. When complete, the reaction was chilled to -70° C. (acetone/ dry ice), whereupon the above isothiocyanate (12.4 g.) in THF (25 ml) was added at once. The temperature rose to -50° C. before cooling to -70° C. After stirring to ambient temperature and leaving overnight a solid had precipitated out. The solvent was removed, water added, washed with ether and acidified. A pale yellow solid had precipitated out. This was collected on a filter, washed with water, dried and recrystallized from IPA to give 2,3 dihydro-3-[3-(1-methylethoxy)-4-methylphenyl]- 2-thioxo-6-(trifluoromethyl)-4(1H)-pyrimidinone, mp. 227°-228°.

Provenance & Evidence