Benzyl Bromide → Racemic (+/-)-methyl 4-(2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-isocyanoethyl)benzoate

HRID 1874289Notes

Reaction equation

HRID 1874289 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)[N+:9]#[C-:10])=[CH:4][C:3]=1[O:25][CH:26]([CH3:28])[CH3:27].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[K+].C[CH2:40][O:41][C:42](C)=[O:43]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[C:15]([O:17][C:18]([F:22])([F:23])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)([N+:9]#[C-:10])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:42]([O:41][CH3:40])=[O:43])=[CH:32][CH:31]=2)=[CH:4][C:3]=1[O:25][CH:26]([CH3:28])[CH3:27]

Participants

7

Reactant 4

HCID 7498Benzyl BromideHCID 8857Ethyl AcetateHCID 14797Potassium HydroxideHCID 594592651-Fluoro-4-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(isocyano)methyl)-2-isopropoxybenzene

Product 1

HCID 72290934Racemic (+/-)-methyl 4-(2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-isocyanoethyl)benzoateYield 79%

Reagents, catalysts & solvents 2

HCID 74236Tetrabutylammonium BromideCatalystHCID 1140TolueneSolvent

Procedure

To a solution of 1-fluoro-4-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(isocyano)methyl)-2-isopropoxybenzene (81 mg, 0.2 mmol) in toluene (2 mL) was added tetrabutylammonium bromide (19 mg, 0.06 mmol) and benzyl bromide (50 mg, 0.22 mmol), followed by 50% KOH(aq) (650 μl). The reaction mixture was vigorously stirred for 3 minutes. The reaction mixture was diluted with EtOAc (20 mL). The organic layer was separated, washed with sat. NaCl (2 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by ISCO (12 g silica gel column, 0-40% EtOAc/hexane over 35 min) to yield racemic (±)-methyl 4-(2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-isocyanoethyl)benzoate as a colorless film (87 mg, 79% yield). LCMS RT=2.24 min [M-NC] 525.1 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0. % TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (2H, d, J=7.47 Hz), 7.08 (1H, t, J=9.67 Hz), 6.93-6.99 (5H, m), 6.87 (2 H, d, J=6.59 Hz), 5.76-6.03 (1H, m), 4.40-4.46 (1H, m), 3.90 (3H, s), 3.65 (2H, s), 1.27 (6H, dd, J=17.58, 5.71 Hz).

Workup

  1. customThe organic layer was separated
  2. washwashed with sat. NaCl (2 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by ISCO (12 g silica gel column, 0-40% EtOAc/hexane over 35 min)

Sources & evidence

ORD record
ord-1ff1a71ab7d04daea2cfaf1e12c62e20
Source dataset
uspto-grants-2012_11
Patent number
US08304403B2

Reaction notes

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