Reaktion #624933

Reaktionsgleichung

NH4OH

sec-BuLi

2-bromo-1,4-difluorobenzene

tert-butylpyrrolidine-1-carboxylate

(−)sparteine

→

(R)-tert-butyl 2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate

Ausbeute 72.2%

Lösungsmittel

MTBE

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigeunder −70° C
2. 2
   Sonstigethe internal temperature below −65° C
3. 3
   workup.STIRRINGThe resulting light suspension was stirred at −78° C. for 30 minutes
4. 4
   Temperaturwarmed to ambient temperature
5. 5
   workup.STIRRINGAfter stirring overnight at ambient temperature
6. 6
   workup.STIRRINGthe reaction was stirred for another hour
7. 7
   FiltrationThe resulting slurry was filtered through CELITE
8. 8
   Waschenwashed with Et2O (1 L)
9. 9
   WaschenThe filtrate was washed with HCl (0.5 L, 1M aq.) and brine
10. 10
    FiltrationThe organic layer was filtered
11. 11
    Einengenconcentrated
12. 12
    Sonstigethe crude product was purified by silica column chromatography
13. 13
    Wascheneluting with 5-10% EtOAc/hexanes

Vorschrift

A solution of tert-butylpyrrolidine-1-carboxylate (20 g, 116.8 mmol) and (−)sparteine (32.9, 140 mmol) in MTBE (360 mL) was cooled to −78° C., and sec-BuLi (100 mL, 140 mmol, 1.4 M in cyclohexane) was introduced dropwise via cannula, keeping the internal temperature under −70° C. The resulting solution was stirred for 3 hours at −78° C., followed by addition of a solution of ZnCl2 (93.4 mL, 93.4 mmol, 1M in Et2O) drop-wise with rapid stirring, keeping the internal temperature below −65° C. The resulting light suspension was stirred at −78° C. for 30 minutes and then warmed to ambient temperature. The resulting mixture was charged with 2-bromo-1,4-difluorobenzene (14.5 mL, 128 mmol), followed by Pd(OAc)2 (1.31 g, 5.8 mmol) and t-Bu3P—HBF4 (2.03 g, 7.0 mmol) in one portion. After stirring overnight at ambient temperature, 10.5 mL of NH4OH solution was added and the reaction was stirred for another hour. The resulting slurry was filtered through CELITE and washed with Et2O (1 L). The filtrate was washed with HCl (0.5 L, 1M aq.) and brine. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5-10% EtOAc/hexanes to give product (R)-tert-butyl 2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate as yellow oil (23.9 g, 72% yield).

Quelle