Cesium carbonate → 4-Chloro-2-(difluoromethyl)-1-{[5-(3,5-difluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indole-5-carbonitrile

HRID 1188327Notes

Reaction equation

HRID 1188327 reaction equation
[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:23][C:24]1[N:28]=[C:27]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=2)[O:26][N:25]=1>CC#N>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:23][C:24]1[N:28]=[C:27]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=2)[O:26][N:25]=1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 249856324-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrileHCID 431202093-(Chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole

Product 1

HCID 247644714-Chloro-2-(difluoromethyl)-1-{[5-(3,5-difluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indole-5-carbonitrileYield 77%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
95 °C

Procedure

To a solution of 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile (0.23 g, 1.0 mmol) in anhydrous MeCN (5 mL) was added Cs2CO3 (0.38 g, 1.15 mmol) and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole (0.27 g, 1.15 mmol). The mixture was heated in a sealed tube at 95° C., under N2, for 1 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (2-30% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.32 g, 77% yield): 1H NMR (400 MHz, acetone-d6) δ 7.91 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.70 (m, 2H), 7.45 (t, J=53.4 Hz, 1H), 7.42 (tt, J=9.0, 2.4 Hz, 1H), 7.20 (s, 1H), 5.95 (s, 2H); MS (ES) m/z 421 (M+1).

Workup

  1. temperatureUpon cooling
  2. customthe mixture was partitioned between EtOAc and water
  3. washThe organic phase was washed with water
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by flash chromatography (2-30% EtOAc-hexanes gradient)
  7. customthe product was crystallized from CH2Cl2-hexanes

Sources & evidence

ORD record
ord-664b33f61b2c4d128d8c34ef6a5828b2
Source dataset
uspto-grants-2014_03
Patent number
US08673948B2

Reaction notes

Loading…