Potassium Carbonate → (R)-1-(1-(3-cyanophenyl)ethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile

HRID 1851133Notes

Reaction equation

HRID 1851133 reaction equation
F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:14]#[C:15][Si](C)(C)C.[NH2:20][C@@H:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])[CH3:22].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:26]([C:25]1[CH:24]=[C:23]([C@H:21]([N:20]2[C:2]3[C:3](=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([C:6]#[N:7])=[CH:8][CH:9]=3)[CH:14]=[CH:15]2)[CH3:22])[CH:30]=[CH:29][CH:28]=1)#[N:27]

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 516892Sodium BicarbonateHCID 21065209(R)-3-(1-aminoethyl)benzonitrileHCID 867091684-Fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile

Product 1

HCID 86709190(R)-1-(1-(3-cyanophenyl)ethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrileYield 41.1%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
60 °C

Procedure

An oven-dried vial was charged with 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (Example 21D) (0.173 g, 0.606 mmol), commercially available (R)-3-(1-aminoethyl)benzonitrile (0.098 g, 0.667 mmol) and K2CO3 (0.092 g, 0.667 mmol) and sealed with a rubber septum. Anhyd NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2 for 17 h. The mixture was cooled, poured into satd NaHCO3 and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (R)-1-(1-(3-cyanophenyl)ethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.0845 g, 41% yield) as a pale yellow gum which solidified upon trituration with Et2O/hexanes: 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=7.6 Hz, 1H), 7.57 (d, J=4.6 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.29 (d, J=6.7 Hz, 1H, overlapping with solvent), 6.96 (m, 1H), 5.76 (q, J=7.0 Hz, 1H), 2.01 (d, J=7.1 Hz, 3H); MS (LCMS ES+) m/z 340 ([M+H]+, 86%), 381 ({[M+H]+MeCN}+, 100%).

Workup

  1. customsealed with a rubber septum
  2. temperatureThe mixture was cooled
  3. extractionextracted with EtOAc (×3)
  4. washCombined organics were washed (water, brine)
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution)

Sources & evidence

ORD record
ord-ec0a4ed6306b4d449a81636732018603
Source dataset
uspto-grants-2015_02
Patent number
US08957104B2

Reaction notes

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