4-Phenyl-2-pyrrolidinone → 1-{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylpyrrolidin-2-one

HRID 1994496Notes

Reaction equation

HRID 1994496 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]1([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[C:35]1[CH:40]=[C:39]([CH:41]([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[O:44][CH3:45]>C1COCC1>[CH:41]([C:39]1[CH:38]=[CH:37][C:36]([O:44][CH3:45])=[C:35]([C:26]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:32])[F:33])=[CH:30][C:25]=2[CH2:24][N:20]2[CH2:21][CH:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:18][C:19]2=[O:22])[CH:40]=1)([CH3:43])[CH3:42]

Participants

5

Reactant 3

HCID 1213974-Phenyl-2-pyrrolidinoneHCID 2724254Sodium bis(trimethylsilyl)amideHCID 533636432-(Bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl

Product 1

HCID 117054191-{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylpyrrolidin-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

Sodium bis(trimethylsilyl)amide (114 μL of a 1M solution in THF, 0.114 mmol) was added to a stirred solution of 4-phenylpyrrolidin-2-one (Winans, C. F., Adkins, H., J. Am. Chem. Soc., 1933, 55, 4167-4176) (17 mg, 0.103 mmol) in dry THF (1 mL) at room temperature under N2. The reaction was stirred for 5 min and a solution of 2-(bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl (20 mg, 0.0516 mmol) in dry THF (2 mL) was added by cannula. The reaction was stirred at room temperature for 3 days. The reaction was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-90% EtOAc in hexanes gradient) to afford 1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylpyrrolidin-2-one as a colorless oil. Rf=0.11 (20% EtOAc/hexanes). LCMS calc.=468.22; found=468.2 (M+1)+. 1H NMR (600 MHz, benzene-d6, 1:1 mixture of atropisomers) δ 7.79 (s, 0.5H), 7.73 (s, 0.5H), 7.33 (d, J=7.7 Hz, 1H), 7.08-7.04 (m, 4H), 6.99 (m, 1H), 6.92 (s, 0.5H), 6.88 (s, 0.5H), 6.76 (dd, J=16.0, 7.4 Hz, 2H), 6.60 (dd, J=8.5, 3.1 Hz, 1H), 4.58 (d, J=15.4 Hz, 1H), 4.38 (t, J=13.9 Hz, 1H), 3.29 (s, 1.5H), 3.26 (s, 1.5H), 2.85-2.73 (m, 3H), 2.63-2.57 (m, 1H), 2.38-2.28 (m, 1H), 2.21-2.11 (m, 1H), 1.20-1.16 (m, 6H).

Workup

  1. stirringThe reaction was stirred at room temperature for 3 days
  2. customThe reaction was quenched with saturated NH4Cl (10 mL)
  3. extractionextracted with EtOAc (3×20 mL)
  4. washThe combined organic extracts were washed with brine (10 mL)
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated in vacuo
  7. customto give the crude product
  8. customThis was purified by flash chromatography (Si, 12×160 mm, 0-90% EtOAc in hexanes gradient)

Sources & evidence

ORD record
ord-2965e6504ec9404cb8ca9db0ec47a761
Source dataset
uspto-grants-2010_01
Patent number
US07652049B2

Reaction notes

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