(R)-tert-butyl 2-((N-methoxy-N-methylcarbamoyl)methyl)-4,4-difluoropyrrolidine-1-carboxylate → (R)-tert-butyl 4,4-difluoro-2-(4-methyl-2-oxopent-3-enyl)pyrrolidine-1-carboxylate

HRID 633347Notes

Reaction equation

HRID 633347 reaction equation
CON(C)[C:4]([CH2:6][C@@H:7]1[CH2:11][C:10]([F:13])([F:12])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5].[CH3:22][C:23]([CH3:27])=[CH:24][Mg]Br>C1COCC1>[F:13][C:10]1([F:12])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:7]([CH2:6][C:4](=[O:5])[CH:22]=[C:23]([CH3:27])[CH3:24])[CH2:11]1

Participants

4

Reactant 2

HCID 86704456(R)-tert-butyl 2-((N-methoxy-N-methylcarbamoyl)methyl)-4,4-difluoropyrrolidine-1-carboxylateHCID 178448304HCID 178448304, compound

Product 1

HCID 86704458(R)-tert-butyl 4,4-difluoro-2-(4-methyl-2-oxopent-3-enyl)pyrrolidine-1-carboxylateYield 79.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a THF (23 ml) solution of (R)-tert-butyl 2-((N-methoxy-N-methylcarbamoyl)methyl)-4,4-difluoropyrrolidine-1-carboxylate (1.4 g, 4.54 mmol) over ice bath, 2-methyl-1-propenylmagnesium bromide solution (0.5 M in THF, 45 ml, 22.7 mmol) was added dropwise over 1 hour. Remove ice bath, stifling was continued for another 3 hours. The reaction was quenched with 1N HCl (aq., 30 ml) at 0° C., and was stirred at room temperature for 30 minutes. Two layers were separated, aqueous layer was extracted with EtOAc (25 ml×2), organic layers were combined, dried (Na2SO4), filtered, solvent was removed in vacuo. Product was purified by silica gel chromatography (Hexane/EtOAc, linear gradient from 100:0 to 80:20). Compound (R)-tert-butyl 4,4-difluoro-2-(4-methyl-2-oxopent-3-enyl)pyrrolidine-1-carboxylate was obtained as a light yellow oil: 1.10 g (79.5% yield).

Workup

  1. customThe reaction was quenched with 1N HCl (aq., 30 ml) at 0° C.
  2. customTwo layers were separated
  3. extractionaqueous layer was extracted with EtOAc (25 ml×2), organic layers
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. customsolvent was removed in vacuo
  7. customProduct was purified by silica gel chromatography (Hexane/EtOAc, linear gradient from 100:0 to 80:20)

Sources & evidence

ORD record
ord-ef5e808584b3492db39b61cb9b951e64
Source dataset
uspto-grants-2016_04
Patent number
US09321763B2

Reaction notes

Loading…