Water → (E)-4-(3,5-bis(trifluoromethyl)phenyl)-1-(3-(3,3-difluoroazetidin-1-yl)-3-oxoprop-1-enyl)pyrrolidin-2-one

HRID 1486991Notes

Reaction equation

HRID 1486991 reaction equation
[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[F:23][C:24]1([F:33])[CH2:27][N:26]([C:28](=[O:32])/[CH:29]=[CH:30]\I)[CH2:25]1.O>CN(C=O)C>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([CH:13]2[CH2:17][N:16](/[CH:30]=[CH:29]/[C:28]([N:26]3[CH2:27][C:24]([F:33])([F:23])[CH2:25]3)=[O:32])[C:15](=[O:18])[CH2:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:8]=1

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 816553704-(3,5-Bis(trifluoromethyl)phenyl)pyrrolidin-2-oneHCID 86730374(Z)-1-(3,3-difluoroazetidin-1-yl)-3-iodoprop-2-en-1-one

Product 1

HCID 86298784(E)-4-(3,5-bis(trifluoromethyl)phenyl)-1-(3-(3,3-difluoroazetidin-1-yl)-3-oxoprop-1-enyl)pyrrolidin-2-oneYield 4.03%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

4-(3,5-bis(trifluoromethyl)phenyl)pyrrolidin-2-one (0.5 g, 1.0 eq.) was dissolved in DMF (5 mL) and cooled to 0° C. A solution of NaH in DMF (0.133 g, 2.0 eq.) was added at 0° C. (Z)-1-(3,3-difluoroazetidin-1-yl)-3-iodoprop-2-en-1-one (0.689 g, 1.5 eq.) was then introduced. The reaction mixture was stirred for 30 min at room temp. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 0.502 g of crude product, which was purified by chromatography (1% Methanol in DCM) to give 0.030 g of (E)-4-(3,5-bis(trifluoromethyl)phenyl)-1-(3-(3,3-difluoroazetidin-1-yl)-3-oxoprop-1-enyl)pyrrolidin-2-one (Yield 4.03%). 1H NMR (400 MHz, CDCl3) δ 8.15-8.19 (d, J=14 Hz, 1H), 7.69-7.87 (m, 3H), 5.27-5.31 (d, J=14 Hz, 1H), 4.05-4.47 (m, 4H), 3.89-3.93 (s, 1H), 3.73-3.77 (s, 1H), 3.60-3.62 (s, 1H), 3.08-3.13 (s, 1H), 2.78-2.90 (s, 1H); LCMS calcd. for C18H14F8N2O2 [M+H]+. found 443.44 at retention time 2.97 min.

Workup

  1. additionwas then introduced
  2. extractionextracted with EtOAc (3×20 mL)
  3. washThe combined organic layers were washed with brine (3×50 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customto afford 0.502 g of crude product, which
  8. customwas purified by chromatography (1% Methanol in DCM)

Sources & evidence

ORD record
ord-9a56a8a3c3d847b3ac2ae6a59c17d9b4
Source dataset
uspto-grants-2016_08
Patent number
US09428490B2

Reaction notes

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