Acetic Acid → 2'-({[Tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-ol

HRID 1994597Notes

Reaction equation

HRID 1994597 reaction equation
C([Li])CCC.[C:6]([Si:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([F:34])=[CH:27][C:26]=1[O:35][CH3:36])([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].B(OC)(OC)[O:38]C.C(O)(=O)C.OO>C1COCC1.O>[Si:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[CH:17][C:16]=1[C:25]1[CH:30]=[C:29]([CH:31]([CH3:32])[CH3:33])[C:28]([F:34])=[C:27]([OH:38])[C:26]=1[O:35][CH3:36])([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:12])[CH3:11]

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 784Hydrogen PeroxideHCID 8470Trimethyl borateHCID 66717161Tert-butyl{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methoxy}dimethylsilaneHCID 178418339Butyllithium

Product 1

HCID 866034342'-({[Tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-ol

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

n-Butyllithium (1.6M in hexanes, 261 μL, 0.417 mmol) was added dropwise over 30-45 min with a syringe pump to a stirred solution of tert-butyl{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methoxy}dimethylsilane (200 mg, 0.438 mmol) in dry THF (0.5 mL) at −78° C. under N2. The reaction was stirred for a further 2 h at −78° C. after the addition to give a violet colored solution. Trimethyl borate (43.4 mg, 47 μL, 0.417 mmol) was added dropwise and the reaction was stirred at −78° C. for 3 h. The reaction mixture was warmed to 0° C. and acetic acid (25.1 mg, 24 μL, 0.626 mmol) was added quickly followed by 30% aqueous hydrogen peroxide (52 μL, 0.459 mmol) dropwise. The reaction was stirred at room temperature overnight, diluted with water (10 mL) and extracted with Et2O (3×20 mL). The combined extracts were washed with 50% saturated FeSO4 (20 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-100% EtOAc in hexanes gradient) to afford 2′-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol. Rf=0.32 (10% EtOAc in hexanes). LCMS calc.=473.1; found=473.2 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 7.95 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 5.65 (s, 1H), 4.68 (br s, 1H), 4.54 (br s, 1H), 3.42 (s, 3H), 3.26-3.20 (m, 1H), 1.25 (d, J=6.9 Hz, 6H), 0.90 (s, 9H), 0.02 (s, 6H).

Workup

  1. additionafter the addition
  2. customto give a violet colored solution
  3. stirringthe reaction was stirred at −78° C. for 3 h
  4. temperatureThe reaction mixture was warmed to 0° C.
  5. stirringThe reaction was stirred at room temperature overnight
  6. extractionextracted with Et2O (3×20 mL)
  7. washThe combined extracts were washed with 50% saturated FeSO4 (20 mL)
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated in vacuo
  10. customto give the crude product
  11. customThis was purified by flash chromatography (Si, 12×160 mm, 0-100% EtOAc in hexanes gradient)

Sources & evidence

ORD record
ord-c880cd737a0c4bafa2be56500d1520ff
Source dataset
uspto-grants-2010_01
Patent number
US07652049B2

Reaction notes

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