Triethylamine → 3-Bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one

HRID 1507232Notes

Reaction equation

HRID 1507232 reaction equation
[Br:1][CH:2]([CH2:6][CH2:7]Br)[C:3](Cl)=[O:4].[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13].CCN(CC)CC.[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][CH:2]1[CH2:6][CH2:7][N:13]([C:12]2[CH:14]=[CH:15][C:16]([CH3:17])=[C:10]([F:9])[CH:11]=2)[C:3]1=[O:4]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 99573-Fluoro-4-methylanilineHCID 24758Sodium hydrideHCID 44131432,4-Dibromobutyryl chloride

Product 1

HCID 637889133-Bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-oneYield 54.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 2,4-dibromobutanoyl chloride (10 g, 38 mmol) in 100 mL of DCM at 0° C. under nitrogen was added 3-fluoro-4-methylaniline (5.21 g, 42 mmol) followed by Et3N (6.3 mL, 45 mmol). The mixture was stirred at rt for 2 h, then concentrated in vacuo. The residue was dissolved in diethyl ether, then hexanes was added and a solid precipitated. The solid was removed by filtration and discarded. The filtrate was then concentrated in vacuo to give a dry residue. To a solution of this residue in 100 mL DMF at 0° C. under nitrogen was slowly added 60% NaH (1.82 g, 45 mmol). The mixture was stirred and allowed to warm up to rt over 30 min. The reaction mixture was slowly poured into 400 mL of icewater and allowed to stand overnight. A solid formed, and was filtered off and dried, then purified via silica gel chromatography eluting with 0-50% ethyl acetate/hexanes to give racemic 3-bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (5.6 g, 20.6 mmol). LCMS (method U) RT 3.41 min, m/z 273.97 (M+H+). 1H NMR (500 MHz, chloroform-d) δ 7.50 (dd, J=11.7, 2.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.23-7.17 (m, 1H), 4.60 (dd, J=7.0, 2.9 Hz, 1H), 4.03 (ddd, J=9.8, 7.9, 6.8 Hz, 1H), 3.82 (ddd, J=10.0, 7.7, 2.7 Hz, 1H), 2.75 (dq, J=14.6, 7.5 Hz, 1H), 2.48 (ddt, J=14.3, 6.7, 2.7 Hz, 1H), 2.28 (d, J=1.7 Hz, 3H).

Workup

  1. concentrationconcentrated in vacuo
  2. dissolutionThe residue was dissolved in diethyl ether
  3. additionhexanes was added
  4. customa solid precipitated
  5. customThe solid was removed by filtration
  6. concentrationThe filtrate was then concentrated in vacuo
  7. customto give a dry residue
  8. customat 0° C.
  9. stirringThe mixture was stirred
  10. temperatureto warm up to rt over 30 min
  11. additionThe reaction mixture was slowly poured into 400 mL of icewater
  12. waitto stand overnight
  13. customA solid formed
  14. filtrationwas filtered off
  15. customdried
  16. custompurified via silica gel chromatography
  17. washeluting with 0-50% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-6908f64a3fe5478e9daea8a0bcfa4377
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

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