Cesium carbonate → 4-{3-[1-(2,2-dimethylpropyl)-4-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]phenoxy}benzonitrile

HRID 882210Notes

Reaction equation

HRID 882210 reaction equation
[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)=[C:12]([F:13])[C:7]=2[N:6]([CH3:21])[C:5]1=[O:22].Br[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.[Cu]I>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)=[C:12]([F:13])[C:7]=2[N:6]([CH3:21])[C:5]1=[O:22]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 12162Benzonitrile, 4-bromo-2×HCID 667491271-(2,2-dimethylpropyl)-4-fluoro-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one

Product 1

HCID 667493404-{3-[1-(2,2-dimethylpropyl)-4-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]phenoxy}benzonitrile

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

A solution of 1-(2,2-dimethylpropyl)-4-fluoro-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (7-15, 55 mg, 0.17 mmol) in NMP (1 ml) was sequentially charged with 4-Bromobenzonitrile (61.0 mg, 0.34 mmol, 2.0 eq), Cesium carbonate (109 mg, 0.34 mmol, 2.0 eq) and Copper(I) iodide (31.9 mg, 0.17 mmol, 1.0 eq). The resulting mixture was irradiated in a microwave at 195 deg C. for 2 h. LC/MS analysis showed only partial conversion, therefore additional amounts of 4-Bromobenzonitrile (61.0 mg, 0.34 mmol, 2.0 eq) and Cu(I)I (31.9 mg, 0.17 mmol, 1.0 eq) were added and the reaction was irradiated again at 195 deg C. for 1 h. The completed reaction was filtered and the filtrate purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present) to afford the title compound, 4-{3-[1-(2,2-dimethylpropyl)-4-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]phenoxy}benzonitrile (9-1), as a tan solid-oil. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 2H, J=8.9 Hz), 7.50-7.46 (m, 1H), 7.39 (m, 1H), 7.25 (s, 1H), 7.09-7.04 (m, 4H), 6.87 (d, 1H, J=8.2 Hz), 3.67 (s, 2H), 3.64 (s, 3H), 1.05 (s, 9H). LRMS m/z: Calc'd for C26H24FN3O2(M+H) 430.2, found 430.5.

Workup

  1. customThe resulting mixture was irradiated in a microwave at 195 deg C
  2. customthe reaction was irradiated again at 195 deg C
  3. waitfor 1 h
  4. customThe completed reaction
  5. filtrationwas filtered
  6. customthe filtrate purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present)

Sources & evidence

ORD record
ord-05ee17c1810641cca4b0d5d7bfce82de
Source dataset
uspto-grants-2015_03
Patent number
US08993779B2

Reaction notes

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