Hydrochloric Acid → 4-(4-Amino-3-nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

Sodium sulfite (1.5 g, 11.9 mmol) and NaHCO3 (1.12 g, 13.3 mmol) were dissolved in water (30 mL) and 4-acetylamino-3-nitro-benzenesulfonyl chloride (1.94 g, 7 mmol) was added. Ethanol (10 mL) and the mixture was stirred for 6 h at rt. Aqueous NaOH (10N, 6 mL, 60 mmol) was added and the reaction was heated to 80° C. for 2 h. The solution was brought to pH˜8 with conc. HCl, and the solvent was removed in vacuo. DMF (15 mL) was added, the mixture was stirred for 15 min, and the inorganic salts were then allowed to settle. The DMF was removed via syringe, the salts were washed with a second portion of DMF (10 mL), and the combined DMF solution was slowly added to a 0° C. solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 931 mg, 3.5 mmol) in DMF (15 mL). The solution was stirred for 0° C. for 1 h then overnight at rt. The DMF was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and aq NaHCO3 (30 mL). The layers were separated and the organic layer was washed with aq NaHCO3 (2×20 mL), water (30 mL), and brine (30 mL), then dried over sodium sulfate. The solution was concentrated and the residue was dissolved in THF (20 mL) and cooled to −78° C. A solution of sodium methoxide in methanol (1M, 7 mL, 7 mmol) was added dropwise and the reaction was stirred for 30 min. Acetic acid (500 μL) was added followed by EtOAc (100 mL). The solution was washed with NaHCO3 (3×30 mL), brine (40 mL), and was dried over sodium sulfate. Concentration and chromatography of the residue yielded the title compound (381 mg, 28%) as a yellow solid. 1H-NMR (CDCl3): δ 10.56 (br s, 2H), 9.04 (d, 1H, J=8.8 Hz), 8.89 (d, 1H, J=2.3 Hz), 8.22 (dd, 1H, J=2.3, 9.1 Hz), 8.04 (s, 1H), 3.90 (s, 3H), 2.64 (s, 3H), 2.35 (s, 3H).

Provenance & Evidence