反应详情

温度

0 °C

To a 0° C. solution of 0.2 g of 2-iodo-5-(trifluoromethyl)benzaldehyde in 3 mL of EtOH was added 0.13 mL of nitromethane, then 0.28 mL of a 2.5 N solution of NaOH. The mixture was stirred at 0° C. for 3 h, and then neutralized by addition of 2.1 mL of a 0.33 N aqueous solution of AcOH. The mixture was partitioned between 10 mL of water and 10 mL of EtOAc. The aqueous phase was extracted with 2×5 mL of EtOAc. The combined organics were washed with 10 mL of brine, dried over Na2SO4, and concentrated. The residue was dissolved in 4 mL of MeOH and 0.5 mL of 88% aqueous formic acid was added. Approximately 200 mg of a Raney nickel slurry was added and the mixture was flushed with H2, and stirred under an H2 balloon for 4 h. The mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated. The residue was partitioned between 10 mL of 10% aqueous NH4OH and 20 mL of EtOAc. The aqueous phase was extracted with 2×10 mL of EtOAc. The combined organics were washed with 10 mL of brine, dried over Na2SO4, and concentrated. The residue was dissolved in 2 mL of CH2Cl2. To the solution was added 0.114 mL of diisopropylethylamine, then 0.065 g of triphosgene. The mixture was stirred at 0° C. for 30 min, then diluted with 10 mL of EtOAc and 10 mL of saturated NaHCO3. The aqueous phase was extracted with 2×10 mL of EtOAc. The combined organics were washed with 10 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 4% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 4 to 100% over 10 CV to provide the title compound. Mass spectrum (ESI) 350.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.00 (d, J=8 Hz, 1H), 7.74 (br s, 1H), 7.33 (br d, J=8 Hz, 1H), 5.80 (dd, J=7 Hz, 9 Hz 1H), 5.05-5.50 (br, 1H), 4.28 (t, J=9 Hz, 1.5H), 3.36 (dd, J=7 Hz, 9 Hz, 1H).

1. customThe mixture was partitioned between 10 mL of water and 10 mL of EtOAc
2. extractionThe aqueous phase was extracted with 2×5 mL of EtOAc
3. washThe combined organics were washed with 10 mL of brine
4. dry with materialdried over Na2SO4
5. concentrationconcentrated
6. dissolutionThe residue was dissolved in 4 mL of MeOH
7. addition0.5 mL of 88% aqueous formic acid was added
8. additionApproximately 200 mg of a Raney nickel slurry was added
9. customthe mixture was flushed with H2
10. stirringstirred under an H2 balloon for 4 h
11. filtrationThe mixture was filtered through a pad of Celite
12. washwashing with MeOH
13. concentrationthe filtrate was concentrated
14. customThe residue was partitioned between 10 mL of 10% aqueous NH4OH and 20 mL of EtOAc
15. extractionThe aqueous phase was extracted with 2×10 mL of EtOAc
16. washThe combined organics were washed with 10 mL of brine
17. dry with materialdried over Na2SO4
18. concentrationconcentrated
19. dissolutionThe residue was dissolved in 2 mL of CH2Cl2
20. additionTo the solution was added 0.114 mL of diisopropylethylamine
21. stirringThe mixture was stirred at 0° C. for 30 min
22. additiondiluted with 10 mL of EtOAc and 10 mL of saturated NaHCO3
23. extractionThe aqueous phase was extracted with 2×10 mL of EtOAc
24. washThe combined organics were washed with 10 mL of brine
25. dry with materialdried over Na2SO4
26. concentrationconcentrated
27. customThe residue was purified by flash chromatography on a Biotage Horizon, 25S column
28. washeluting with 1 CV of 4% EtOAc in hexanes