Diethyl Ether → (R)-tert-butyl 2-(3-fluoro-4-(trifluoromethyl)benzoyl)-pyrrolidine-1-carboxylate

HRID 2279456Notes

Reaction equation

HRID 2279456 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1.CCOCC.C([Li])CCC.CON(C)[C:26]([C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:27]>C1COCC1>[F:12][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[C:8]([F:11])([F:10])[F:9])[C:26]([C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:27]

Participants

6

Reactant 4

HCID 3283Diethyl EtherHCID 688299HCID 688299, compoundHCID 27829044-Bromo-2-fluorobenzotrifluorideHCID 178418339Butyllithium

Product 1

HCID 71247670(R)-tert-butyl 2-(3-fluoro-4-(trifluoromethyl)benzoyl)-pyrrolidine-1-carboxylateYield 35%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (4.854 g, 19.98 mmol) and ether (50 mL) cooled to −78° C. was added butyl lithium (7.990 mL, 19.98 mmol) slowly over 10 min. The reaction was transferred via cannula to a solution of 74 (4.30 g, 16.65 mmol) in THF (50 mL) cooled to −78° C. The reaction was stirred for 10 min after all aryl lithium was added. The reaction was quenched with water and extracted with DCM. The organic layer was concentrated and the crude product purified by SiO2 chromatography eluting with an EtOAc/hexane (1 to 5% EtOAc). A close running impurity was not removed by this purification. A SiO2 column was run eluting with an Et2O/hexane gradient (1 to 3% Et2O). The impurity was still present and the compound was finally purified on a SP4 reverse phase column chromatography eluting with MeCN/water gradient (65 to 100% MeCN) to afford 2.105 g (33.2%) of (R)-tert-butyl 2-(3-fluoro-4-(trifluoromethyl)benzoyl)-pyrrolidine-1-carboxylate (76).

Workup

  1. additionwas added
  2. customThe reaction was quenched with water
  3. extractionextracted with DCM
  4. concentrationThe organic layer was concentrated
  5. customthe crude product purified by SiO2 chromatography
  6. washeluting with an EtOAc/hexane (1 to 5% EtOAc)
  7. customwas not removed by this purification
  8. washA SiO2 column was run eluting with an Et2O/hexane gradient (1 to 3% Et2O)
  9. customthe compound was finally purified on a SP4 reverse phase column chromatography
  10. washeluting with MeCN/water gradient (65 to 100% MeCN)

Sources & evidence

ORD record
ord-f5cb3ac9e2e14bca916f55fa7f956b94
Source dataset
uspto-grants-2015_09
Patent number
US09133187B2

Reaction notes

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