Potassium Carbonate → 3-{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-6-phenyl-1,3-oxazinan-2-one

HRID 537986Notes

Reaction equation

HRID 537986 reaction equation
I[C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[C:33]([C:2]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=2[CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[CH:32]=1)([CH3:36])[CH3:35]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 45891905-Isopropyl-2-methoxyphenylboronic acidHCID 575443563-[2-Iodo-5-(trifluoromethyl)benzyl]-6-phenyl-1,3-oxazinan-2-one2×

Product 1

HCID 166578193-{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-6-phenyl-1,3-oxazinan-2-one

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 180AcetoneSolventHCID 962WaterSolvent

Procedure

A mixture of 3-[2-iodo-5-(trifluoromethyl)benzyl]-6-phenyl-1,3-oxazinan-2-one (Intermediate 1, 51 mg, 0.11 mmol), 2-methoxy-5-isopropylphenyl boronic acid (86 mg, 0.11 mmol), potassium carbonate (76 mg, 0.55 mmol) and palladium acetate (7.4 mg, 0.011 mmol) in acetone (5 mL) and H2O (1 mL) was degassed and heated at reflux under N2 for 1 h. The reaction mixture was concentrated, diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography on silica gel (0-20% EtOAc in hexanes gradient) to afford 3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-6-phenyl-1,3-oxazinan-2-one as a colorless solid. LCMS=484.2 (M+1)+. 1H NMR present (500 MHz, CDCl3): δ 7.69 (br d, J=3.5 Hz, 1H), 7.62 (br d, J=8.0 Hz, 1H), 7.41-7.30 (m, 5H), 7.28 (d, J=2.5 Hz, 1H), 7.26 (d, J=2.5 Hz, 1H), 7.02 (d, J=2.3 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 5.24 (dd, J=9.6, 2.5 Hz, 1H), 4.68 (d, J=3.2 Hz, 1H), 4.59 (d, J=15.5 Hz, 1H), 3.81 (s, 3H), 3.18-3.04 (m, 1H), 3.04-2.88 (m, 2H), 2.11 (m, 1H), 2.02 (m, 1H), 1.12 (d, J=7.1 Hz, 6H). The racemic material was separated by chiral HPLC using 15% IPA/heptane and an AD column.

Workup

  1. customwas degassed
  2. temperatureheated
  3. temperatureat reflux under N2 for 1 h
  4. concentrationThe reaction mixture was concentrated
  5. additiondiluted with water (10 mL)
  6. extractionextracted with EtOAc (3×20 mL)
  7. dry with materialThe combined extracts were dried (Na2SO4)
  8. concentrationconcentrated in vacuo
  9. customto give the crude product
  10. customThis was purified by flash chromatography on silica gel (0-20% EtOAc in hexanes gradient)

Sources & evidence

ORD record
ord-68feccb7bbaa440fa6e801e77708b1a8
Source dataset
uspto-grants-2014_10
Patent number
US08865707B2

Reaction notes

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