| 31% |
Stage #1: at 0 - 10℃; for 1.25 h;
Stage #2: at 20℃; Reflux |
Example 12: Synthesis of 4-[dimethylamino)diazenyl]thiophene-2-carboxamide (compound 12); Step a:4-Nitrothiophene-2-carboxylic acid: Sulfuric acid (3.0 mL, 5.505 g, 56.17 mmol) was added to nitric acid (2.0 mL, 2.98 g, 49.6 mmol) slowly at 0-10 0C. After completion of the addition, thiophene-2-carboxylic acid (2.8 g, 21.87 mmol) was added to the above nitration mixture slowly for 15 min at the same temperature and stirred the mixture for 1 h. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitated solid was filtered, washed with cold water and dried. The filtrate was extracted with ethyl acetate. The combined ethyl acetate layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The combined product was stirred with hexane (2 x 50 mL) and filtered the solid and dried to give the product as an off-white solid (2.8 g, 75percent), mp 110-118 0C. The product was a mixture of two compounds by HPLC and 1H NMR and was proceeded to the next step. Step b:Methyl 4-nitrothiophene-2-carboxylate: To a solution of nitrothiophene-2-carboxylic acids (6.8 g, 39.3 mmol) in methanol (50 mL) was added thionyl chloride (6 mL, 78.6 mmol) drop wise under stirring at rt. The reaction mixture was refluxed for 2 h and attained to rt. The mixture was poured into ice cooled water and stirred for 15 min. The precipitated solid was filtered, washed with cold water and dried to give the product as an off-white solid (6.2 g, 85percent). 1H NMR showed that, it is a mixture of two compounds and the crude product was proceded to the next step.; Step c:Methyl 4-aminothiophene-2-carboxylate: To a solution of methyl nitrothiophene-2- carboxylates (7 g, 37.43 mmol) in a mixture of water (150 mL) and methanol (50 mL) was added Cone, hydrochloric acid (4.5 mL). To the above solution was added iron powder (10.5 g, 188 mmol) followed by ammonium chloride (1O g, 187 mmol) at rt. The reaction mixture was stirred and warmed to 70 0C for 1 h and was then allowed to cool to rt. The solution was filtered and basified with saturated sodium bicarbonate solution. The solution was extracted with chloroform (4 x 100 mL). The combined organic layer was dried over sodium sulfate and filtered. Solvent was evaporated and the residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10 and small amount of triethyl amine) as eluent to give methyl 4-aminothiophene-2-carboxylate (1.8 g, 31percent), mp 76-780C. 1H NMR (400 MHz, CDCl3): δ 7.31 (IH, d, JH .6 Hz), 6.40 (IH, d, J=I.6 Hz), 3.85 (3H, s), 3.63 (2H, br s).Further elution of the column with the same solvent system provided methyl 5- aminothiophene-2-carboxylate (0.5 g, 8.5percent), mp 70-720C. 1H NMR (400 MHz, CDCl3): δ 7.45 (IH, d, J=4.0 Hz), 6.09 (IH, d, J=4.0 Hz), 4.29 (2H, br s), 3.81 (3H, s). |
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