| 90% |
With sulfuric acid; In water; for 1h;Heating / reflux; |
The product of preparation 22 (4.69g, 15.4mmol) and dilute sulphuric acid (24%, 120mL) were heated under reflux for 1 hour. The mixture was then cooled, basified with solid sodium hydrogen carbonate to pH8 and extracted with dichloromethane (3x200mL). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluding with dichloromethane:methanol, 100:0 to 90:10, afforded the title compound as a brown solid in 90% yield, 3.04g. 1H-NMR(CDCl3, 400MHz) δ: 4.11 (bs, 2H), 7.56(d, 1H), 7.61 (d, 1H), 8.05(s, 1H) MS APCI+ m/z 221 [MH]+ |
| 75% |
|
The reaction was performed according to a procedure in the literature (Tetrahedron Lett. 2005, 46, 6363). A 1 L three-neck round-bottom flask was equipped with a mechanical stirrer, thermocouple, nitrogen inlet, and drying tube and placed in a heating mantle. The flask was charged with N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide (43, 45 g) and 25% sulfuric acid (270 mL). The solubility of starting material in 25% sulfuric acid was very high and formed light yellow clear solution. The reaction mixture was heated to 80 C. for 8 h. The reaction mixture was stirred continually at 80 C. until deemed to be complete, i.e., upon complete disappearance of starting material (N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide, 43). If reaction was not complete, stirring was continued at 80 C. for additional 6 h then monitored again, and repeated until complete. Typically, reaction was complete within 4-6 h. The reaction was monitored by TLC (SiO2, 100% EtOAc, UV) by partitioning an aliquot of reaction mixture (1 mL) between 50% NaOH solution (2 mL) and EtOAc (4 mL), agitating, allowing the layers to separate, and spotting the organic layer on TLC. The starting material (N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide, 43) had an RF of 0.55, and the product (4-iodo-3-pyridylamine, 44) had an RF of 0.35. Materials used to synthesize 4-iodo-3-pyridylamine (44) are shown in Table 35.To isolate the product (4-iodo-3-pyridylamine, 44), the flask was cooled to -10 C. and the mixture was cautiously basified (pH 10-11) with 50% NaOH solution (45 g) while maintaining a temperature below 10 C. Additional ethyl acetate (200 mL) was added, the reaction was stirred for 10 minutes, and the layers were allowed to separate. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over MgSO4 and charcoal, filtered through a glass fiber filter paper, and concentrated to dryness. The residue was diluted with MTBE (50 mL) and the solids were filtered, rinsing with MTBE (10 mL). The product was air-dried for 2 h and then dried under high vacuum at room temperature to constant weight.4-Iodo-3-pyridylamine (44, lot No. 1358-86-1) was an off-white solid, synthesized with a yield of 24 g (75%). 4-Iodo-3-pyridylamine (44) was analyzed using HPLC (PLX-LC3, 220), and according to results, it was 100% pure. 1H-NMR (300 MHz, CDCl3) was used to confirm the identity of 4-iodo-3-pyridylamine (44). |
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