反应详情

温度

-70 °C

To a 2 L 3-neck round bottom flask outfitted with an addition funnel and thermometer were added anhydrous THF (700 mL) and NaH (60 wt %, 3.90 g, 97.5 mmol). The suspension was cooled in an isopropanol/dry ice bath until the internal temperature was about −20° C. (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (20.0 g, 92.9 mmol) dissolved in anhydrous THF (300 mL) was added dropwise via the addition funnel maintaining the internal temperature between −20° C. to −15° C. Once the addition was complete, the reaction was stirred for 45 minutes at a temperature between 0° C. to 10° C. The reaction was then cooled to −70° C. and a solution of 2,6-dinitrobenzonitrile (19.9 g, 103 mmol) in anhydrous DMF (200 mL) was added dropwise via the addition funnel. The reaction was allowed to warm up gradually to room temperature overnight and THF was removed under reduced pressure. The remaining solution was cooled in an ice bath and treated with a cooled saturated NH4Cl solution (200 mL). The resulting mixture was diluted with EtOAc and successively washed with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to afford crude (S)-tert-butyl 3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (41.74 g) as an orange solid. MS 262 (MH+-Boc). This material was used without purification in the next step.

1. customTo a 2 L 3-neck round bottom flask outfitted with an addition funnel
2. temperatureThe suspension was cooled in an isopropanol/dry ice bath until the internal temperature
3. customwas about −20° C.
4. additionwas added dropwise via the addition funnel
5. temperaturemaintaining the internal temperature between −20° C. to −15° C
6. additionOnce the addition
7. temperatureto warm up gradually to room temperature overnight
8. customTHF was removed under reduced pressure
9. temperatureThe remaining solution was cooled in an ice bath
10. additiontreated with a cooled saturated NH4Cl solution (200 mL)
11. additionThe resulting mixture was diluted with EtOAc
12. washsuccessively washed with water and brine
13. dry with materialThe organic layer was dried over Na2SO4
14. filtrationfiltered
15. customevaporated under reduced pressure