反应详情

2-Chloro-5-iodoaniline (630 mg, 2.49 mmol) was heated at reflux in acetic acid (7 ml) and acetic anhydride (7 ml) for 18 hours. The solution was concentrated in vacuo, azeotroping with toluene. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase separated and washed with saturated aqueous sodium bicarbonate solution, water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a mixture of the mono- and di-acylated acetamide (N-(2-chloro-5-iodophenyl)acetamide and N-acetyl-N-(2-chloro-5-iodophenyl)acetamide). To this product (820 mg) in 1,4-dioxane (12 ml) was added cis-2,6-dimethyl piperazine (416 mg, 3.64 mmol), sodium tert-butoxide (700 mg, 7.29 mmol), tris(dibenzylideneacetone)dipalladium(0) (45 mg, 0.049 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (39 mg, 0.098 mmol) and the reaction heated at reflux for 18 hours under argon. The reaction mixture was cooled, diluted with ethyl acetate (30 ml) and stirred with a mixture of celite and charcoal. The solution was filtered through celite washing with ethyl acetate. The filtrate was concentrated in vacuo, and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was washed with water, 50% saturated brine solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was treated with 5N HCl (20 ml) and heated at reflux for 24 hours under argon. The reaction was cooled, and the solution washed with ethyl acetate (×3), poured onto ice, basified with 0.880 ammonia and extracted with dichloromethane (×4). The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (gradient of 2% to 10% methanol in dichloromethane) to afford the title compound (D34). MS (ES+) m/e 240/242 [M+H]+.

1. concentrationThe solution was concentrated in vacuo
2. customazeotroping with toluene
3. customThe residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution
4. customThe organic phase separated
5. washwashed with saturated aqueous sodium bicarbonate solution, water, brine
6. dry with materialdried over anhydrous magnesium sulfate
7. concentrationconcentrated in vacuo
8. customto afford
9. temperaturethe reaction heated
10. temperatureat reflux for 18 hours under argon
11. temperatureThe reaction mixture was cooled
12. filtrationThe solution was filtered
13. washthrough celite washing with ethyl acetate
14. concentrationThe filtrate was concentrated in vacuo
15. customthe residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution
16. washThe organic phase was washed with water, 50% saturated brine solution, brine
17. dry with materialdried over anhydrous sodium sulfate
18. concentrationconcentrated in vacuo
19. additionThe residue was treated with 5N HCl (20 ml)
20. temperatureheated
21. temperatureat reflux for 24 hours under argon
22. temperatureThe reaction was cooled
23. washthe solution washed with ethyl acetate (×3)
24. additionpoured onto ice
25. extractionextracted with dichloromethane (×4)
26. washThe combined extracts were washed with water, brine
27. dry with materialdried over anhydrous sodium sulfate
28. concentrationconcentrated in vacuo
29. customThe residue was purified by chromatography on silica gel (gradient of 2% to 10% methanol in dichloromethane)