反应详情

To a solution of 5-hydroxy-3-methylpicolinonitrile (0.487 g, 3.63 mmol) in DMF (5 mL) were added cesium carbonate (1.538 g, 4.72 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.011 ml, 4.36 mmol) and the resulting suspension was stirred at rt overnight. The reaction was diluted with water and EtOAc. The organic layer was washed with 1M LiCl solution and brine before drying over magnesium sulfate and concentrating under reduced pressure. The material was taken up in EtOH (20 mL) and NaOH, 1.0M aq (10.89 ml, 10.89 mmol) was added. The reaction was heated to 80° C. and stirred for 6 hours. The reaction was heated to reflux and stirred overnight. The reaction was continued at reflux for a total of 4 days. The reaction was cooled to rt and diluted with ether and water. The organic layer was washed with additional water and the combined aqueous layers were acidified to pH=1 (pH paper) by the addition of 1M HCl. The aqueous layer was extracted with DCM (2×) and the combined organics were brined, dried over magnesium sulfate and concentrated under reduced pressure to afford 3-methyl-5-(2,2,2-trifluoroethoxy)picolinic acid (0.754 g, 3.21 mmol, 88% yield). LC/MS (ESI+) m/z=236 (M+H).

1. washThe organic layer was washed with 1M LiCl solution and brine
2. dry with materialbefore drying over magnesium sulfate
3. concentrationconcentrating under reduced pressure
4. additionNaOH, 1.0M aq (10.89 ml, 10.89 mmol) was added
5. temperatureThe reaction was heated to 80° C.
6. stirringstirred for 6 hours
7. temperatureThe reaction was heated
8. temperatureto reflux
9. stirringstirred overnight
10. temperatureat reflux for a total of 4 days
11. temperatureThe reaction was cooled to rt
12. additiondiluted with ether and water
13. washThe organic layer was washed with additional water
14. additionthe combined aqueous layers were acidified to pH=1 (pH paper) by the addition of 1M HCl
15. extractionThe aqueous layer was extracted with DCM (2×)
16. dry with materialdried over magnesium sulfate
17. concentrationconcentrated under reduced pressure