Hydrochloric Acid → (3-(Tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone

HRID 1874236Notes

Reaction equation

HRID 1874236 reaction equation
Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[Si:21]([O:28][C:29]1[CH:30]=[C:31]([CH:38]=[CH:39][C:40]=1[F:41])[C:32](N(OC)C)=[O:33])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].Cl>CCOCC>[Si:21]([O:28][C:29]1[CH:30]=[C:31]([C:32]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=2)=[O:33])[CH:38]=[CH:39][C:40]=1[F:41])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 236551051-Bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzeneHCID 594586793-((tert-Butyldimethylsilyl)oxy)-4-fluoro-N-methoxy-N-methylbenzamideHCID 178418339Butyllithium

Product 1

HCID 59458571(3-(Tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanoneYield 71%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Procedure

At −78° C. under argon, to a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (2.04 g, 7.01 mmol) in anhydrous ether (20 mL) was added nBuLi (3.5 mL, 2.0 M in cyclohexane, 7.0 mmol) dropwise and the reaction mixture was stirred for 1 h. 3-(Tert-butyldimethylsilyloxy)-4-fluoro-N-methoxy-N-methylbenzamide (2.00 g, 6.38 mmol) was added in one portion and the reaction mixture was stirred at −78° C. for 1.5 h. The pale yellow solution was poured into 1 N HCl aqueous solution (30 mL) and ether (30 mL) was used to rinse the reaction flask. The aqueous phase was separated and extracted with ether (20 mL). The combined ether portions were dried over Na2SO4, filtered and concentrated. The resulting oil was purified by ISCO chromatography (120 g column) using hexanes/EtOAc (0-100% over 30 min) to give (3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone at a retention time of 7 min (2.11 g, 71% yield). LCMS: RT=2.41 min [M+H] 465.19 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.33 ppm, 3H, m; 7.28 ppm, 1H, m; 7.11 ppm, 2H, m; 5.86 ppm, 1H, t, J=53.39 Hz; 0.95 ppm, 9H, s; 0.15 ppm, 6H, s.

Workup

  1. stirringthe reaction mixture was stirred at −78° C. for 1.5 h
  2. washto rinse the reaction flask
  3. customThe aqueous phase was separated
  4. extractionextracted with ether (20 mL)
  5. dry with materialThe combined ether portions were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe resulting oil was purified by ISCO chromatography (120 g column)
  9. customhexanes/EtOAc (0-100% over 30 min)

Sources & evidence

ORD record
ord-50d9d64faa3a45e498f396105351588c
Source dataset
uspto-grants-2012_11
Patent number
US08304403B2

Reaction notes

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