Sodium hydride → (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazinan-2-one

HRID 537973Notes

Reaction equation

HRID 537973 reaction equation
[H-].[Na+].[F:3][C:4]([F:24])([F:23])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:20][C:19](=[O:21])[NH:18][C@@H:17]([CH3:22])[CH2:16]2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[I:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[CH2:36]O>C1COCC1>[F:24][C:4]([F:3])([F:23])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:20][C:19](=[O:21])[N:18]([CH2:36][C:27]3[CH:28]=[C:29]([C:32]([F:33])([F:35])[F:34])[CH:30]=[CH:31][C:26]=3[I:25])[C@@H:17]([CH3:22])[CH2:16]2)[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 23160665(2-Iodo-5-(trifluoromethyl)phenyl)methanol2×HCID 57544409(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one2×

Product 1

HCID 57544352(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazinan-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a stirred suspension of sodium hydride (60% in oil; 5.6 mg; 0.139 mmol) in THF (0.5 mL) at 0° C. under an atmosphere of N2 was added a solution of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 22; 50 mg; 0.153 mmol) in THF (1 mL) dropwise. The resultant mixture stirred at 0° C. for 15 min prior to dropwise addition of 2-(bromomethyl)-1-iodo-4-trifluoromethyl)benzene (Intermediate 11; 50.7 mg; 0.139 mmol) as a solution in THF (0.5 mL). The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was quenched with H2O and partitioned between EtOAc (25 mL) and H2O (15 mL). The aqueous layer was re-extracted with EtOAc (3×25 mL) and the combined extracts were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazinan-2-one as a clear oil. LCMS=611.7 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.02 (d, J=8.2 Hz, 1H), 7.91 (s, 2H), 7.89 (s, 1H), 7.52 (s, 1H), 7.29-7.26 (m, 1H), 5.44 (d, J=10.8 Hz, 1H), 4.88 (d, J=16.5 Hz, 1H), 4.62 (d, J=16.5 Hz, 1H), 3.77-3.70 (m, 1H), 2.45 (dd, J=14.1, 5.4 Hz, 1H), 2.06-1.98 (m, 1H), 1.22 (d, J=6.2 Hz, 3H).

Workup

  1. customThe reaction was quenched with H2O
  2. custompartitioned between EtOAc (25 mL) and H2O (15 mL)
  3. extractionThe aqueous layer was re-extracted with EtOAc (3×25 mL)
  4. washthe combined extracts were washed with brine (25 mL)
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient)

Sources & evidence

ORD record
ord-72128e838ad64e39a5485e18ab60ac44
Source dataset
uspto-grants-2014_10
Patent number
US08865707B2

Reaction notes

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