Potassium tert-butoxide → HCID 86709192, compound

HRID 1851135Notes

Reaction equation

HRID 1851135 reaction equation
[F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.CC([O-])(C)C.[K+].CS(O[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)[CH2:28][CH3:29])(=O)=O>C1COCC1.CCOC(C)=O>[C:36]([C:32]1[CH:31]=[C:30]([CH:27]([N:7]2[C:8]3[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH2:28][CH3:29])[CH:35]=[CH:34][CH:33]=1)#[N:37]

Participants

6

Reactant 3

HCID 23665647Potassium tert-butoxideHCID 674054494-(trifluoromethyl)-1H-indole-5-carbonitrileHCID 86709191HCID 86709191, compound2×

Product 1

HCID 86709192HCID 86709192, compoundYield 27.7%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Procedure

To a suspension of 4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.030 g, 0.143 mmol) in THF (5 mL) was added KOtBu (1M in THF) (0.157 mL, 0.157 mmol). After stirring at rt for a couple of min, a solution of 1-(3-cyanophenyl)propyl methanesulfonate (0.0512 g, 0.214 mmol) in THF (1 mL) was added, and the mixture was heated at 80° C. in a sealed tube. The reaction was monitored by LCMS. After ˜30 min, additional 1-(3-cyanophenyl)propyl methanesulfonate (0.0342 g, 0.143 mmol) in THF (1 mL) was added, and the mixture was heated at 80° C. for another 30 min. Upon cooling, the reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using 0-25% EtOAc-hexane gradient. The material was further purified by preparative HPLC (Phenomenex Luna column; gradient: 10-100% MeCN-water with 0.1% TFA). The fractions with product were combined and concentrated down to the aqueous phase, which was then partitioned between EtOAc (25 mL) and saturated aq. NaHCO3 solution (20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give 1-(1-(3-cyanophenyl)propyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.014 g, 26% yield): MS (ESI): m/z 354 (M+H).

Workup

  1. temperaturethe mixture was heated at 80° C. in a sealed tube
  2. temperaturethe mixture was heated at 80° C. for another 30 min
  3. temperatureUpon cooling
  4. washwashed with water (20 mL)
  5. washThe organic phase was washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was chromatographed over silica gel using 0-25% EtOAc-hexane gradient
  10. customThe material was further purified by preparative HPLC (Phenomenex Luna column; gradient: 10-100% MeCN-water with 0.1% TFA)
  11. concentrationconcentrated down to the aqueous phase, which
  12. customwas then partitioned between EtOAc (25 mL) and saturated aq. NaHCO3 solution (20 mL)
  13. washThe organic phase was washed with brine
  14. dry with materialdried over Na2SO4
  15. filtrationfiltered
  16. concentrationconcentrated

Sources & evidence

ORD record
ord-246b4aa6d1fc47cd8560aaa025795ddd
Source dataset
uspto-grants-2015_02
Patent number
US08957104B2

Reaction notes

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