Benzyl Bromide → Benzyl 5-cyano-2-(trifluoromethyl)benzoate

HRID 889531Notes

Reaction equation

Cl[C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[C:30]([N:32](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:30]([C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:8])#[N:32]

Participants

Conditions

Temperature: 95 °C

Procedure

Under a nitrogen atmosphere, to a solution of 5-chloro-2-(trifluoromethyl)benzoic acid (5.02 g, 22.35 mmol, 1.0 equiv) in DMA (45 mL), add zinc(II) cyanide (1.77 g, 15.07 mmol, 0.67 equiv), zinc dust (<10 μM, 330 mg, 5.05 mmol, 0.23 equiv), and bis(tri-tert-butylphosphino)palladium (540 mg, 1.06 mmol, 0.05 equiv). Stir the mixture under a nitrogen atmosphere at 95° C. for 9.5 hours. Add cesium carbonate (13.3 g, 40.82 mmol, 1.83 equiv), then benzyl bromide (3.0 mL, 25.15 mmol, 1.13 equiv), and stir under air at room temperature for 3.5 hours. Concentrate under reduced pressure, add water, and extract with EtOAc. Separate the organic phase and wash with saturated aqueous NaCl, dry over MgSO4, filter, and concentrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel eluting with a 0-50% EtOAc/hexanes gradient to give the title compound (3.9 g, 57%). MS (m/z) 306 (M+1).

Workup

concentrationConcentrate under reduced pressure
additionadd water
extractionextract with EtOAc
customSeparate the organic phase
washwash with saturated aqueous NaCl
dry with materialdry over MgSO4
filtrationfilter
concentrationconcentrate under reduced pressure

Sources & evidence

ORD record: ord-060b2d212a454d7caae7414001d59693
Source dataset: uspto-grants-2012_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08252831B2

Reaction notes

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