(2S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid → (2S)-1-((tert-butoxy)carbonyl)-4-methylidenepyrrolidine-2-carboxylic acid

HRID 387207Notes

Reaction equation

HRID 387207 reaction equation
[CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=O)[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC1CCCO1>[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=[CH2:1])[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]

Participants

5

Reactant 2

HCID 11593804(2S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acidHCID 23665647Potassium tert-butoxide

Product 1

HCID 21727417(2S)-1-((tert-butoxy)carbonyl)-4-methylidenepyrrolidine-2-carboxylic acid

Reagents, catalysts & solvents 2

HCID 74505Methyltriphenyliphosphonium bromideCatalystHCID 73012-MethyltetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a suspension of methyltriphenylphosphonium bromide (2.2 eq.) in 2-methyl tetrahydrofuran (3 vol) was added rapidly solid potassium tert-butoxide (2.3 eq.) maintaining the temperature around 0° C. The temperature was kept at +20° C. for 2 hours (a suspension remained) and re-cooled to 0° C. Keeping the temperature below 6° C., (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (1 eq.) was added over 40 minutes. The reaction was warmed to room temperature and stirred for 16 h and then cooled to 0° C. The reaction was quenched with saturated NaHCO3 (5 vol) and water (2 vol) and the aqueous layer was separated. The organic layer was extracted with saturated NaHCO3/water (1.8 vol/1.8 vol) and the combined aqueous layers were filtered through Celite®. The aqueous layer was acidified with 6 N HCl (2.6 vol) at ambient temperature and extracted twice with isopropyl acetate (16 vol, then 8 vol). The organic phase was dried (MgSO4) and the solvent removed. The crude product was dissolved in isopropyl acetate (10 vol) and extracted with 0.5 M NaOH (10 vol, then 1 vol). The combined aqueous layers were acidified at ambient temperature with 6 N HCl to pH=3, and extracted twice with ethyl acetate (10 vol, then 8 vol). The combined extracts were dried (Na2SO4), the solvent removed and the crude product was recrystallized from cyclohexane (5 vol) to afford the title compound. 1H-NMR (400 MHz, DMSO): δ 12.9, (broad, 1H); 5.00 (m, 2H); 4.24 (dt, J=1.9H, J=7.3 Hz, 1H), 3.91 (m, 2H); 2.98 (m, 1H); ≈2.50 (m, 1H, coincides with DMSO); 1.41 and 1.36 (2 s rotamers, 9H).

Workup

  1. temperaturere-cooled to 0° C
  2. additionwas added over 40 minutes
  3. temperatureThe reaction was warmed to room temperature
  4. temperaturecooled to 0° C
  5. customThe reaction was quenched with saturated NaHCO3 (5 vol) and water (2 vol)
  6. customthe aqueous layer was separated
  7. extractionThe organic layer was extracted with saturated NaHCO3/water (1.8 vol/1.8 vol)
  8. filtrationthe combined aqueous layers were filtered through Celite®
  9. customwas acidified with 6 N HCl (2.6 vol) at ambient temperature
  10. extractionextracted twice with isopropyl acetate (16 vol
  11. dry with materialThe organic phase was dried (MgSO4)
  12. customthe solvent removed
  13. dissolutionThe crude product was dissolved in isopropyl acetate (10 vol)
  14. extractionextracted with 0.5 M NaOH (10 vol
  15. customwere acidified at ambient temperature with 6 N HCl to pH=3
  16. extractionextracted twice with ethyl acetate (10 vol
  17. dry with materialThe combined extracts were dried (Na2SO4)
  18. customthe solvent removed
  19. customthe crude product was recrystallized from cyclohexane (5 vol)

Sources & evidence

ORD record
ord-3b345fd97f7c4b18a16000529541c6ea
Source dataset
uspto-grants-2013_02
Patent number
US08372873B2

Reaction notes

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