Sodium hydride → (S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-(difluoromethyl)benzyl)pyrrolidin-2-one

HRID 716083Notes

Reaction equation

HRID 716083 reaction equation
[H-].[Na+].[Si:3]([O:10][C@H:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([F:27])[F:26])=[CH:21][CH:20]=1>C1COCC1>[Si:3]([O:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([F:27])[F:26])=[CH:21][CH:20]=2)[C:12]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 10584804(S)-3-((tert-Butyldimethylsilyl)oxy)pyrrolidin-2-one2×HCID 575899071-(Bromomethyl)-4-(difluoromethyl)benzene

Product 1

HCID 123626683(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-(difluoromethyl)benzyl)pyrrolidin-2-oneYield 35%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A 60% dispersion of sodium hydride in mineral oil (232 mg, 5.31 mmol) was added to a stirred solution of (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (762 mg, 3.54 mmol, intermediate G) in THF (7 mL) at 0° C. After 15 min, a solution of 1-(bromomethyl)-4-(difluoromethyl)benzene (980 mg, 4.43 mmol) in THF (7 mL) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 6 h. The reaction was carefully quenched with several grams of ice pellets. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified using silica gel column chromatography (0-30% EtOAc/hexanes) to afford the desired product (440 mg, 35% yield) as a white solid: LCMS (M+H)+ 356.3; 1H NMR (500 MHz, chloroform-d) δ 7.49 (d, J=8.1 Hz, 2H), 7.35 (d, J=7.9 Hz, 2H), 6.65 (br. t, J=1.0 Hz, 1H), 4.56-4.44 (m, 2H), 4.38 (t, J=7.5 Hz, 1H), 3.27 (ddd, J=9.7, 8.7, 3.4 Hz, 1H), 3.13 (dt, J=9.7, 7.4 Hz, 1H), 2.36-2.27 (m, 1H), 1.98-1.90 (m, 1H), 0.96 (br. s., 9H), 0.22-0.20 (m, 3H), 0.20-0.18 (m, 3H).

Workup

  1. customThe reaction was carefully quenched with several grams of ice pellets
  2. extractionThe resulting mixture was extracted with EtOAc
  3. washThe combined organic layers were washed with water
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude reaction mixture
  8. customwas purified

Sources & evidence

ORD record
ord-004b5fabe35e4b3bbcf1ddb323a444e4
Source dataset
uspto-grants-2015_11
Patent number
US09187506B2

Reaction notes

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