Tetrabutylammonium Fluoride → 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile

HRID 1188326Notes

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:22]([F:24])[F:23])[N:6]2S(C1C=CC=CC=1)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[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:22]([F:23])[F:24])[NH:6]2

Participants

Conditions

Temperature: 75 °C

Procedure

To a solution of 4-chloro-2-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-5-carbonitrile (1.05 g, 2.85 mmol) in anhydrous THF (12 mL) under N2, was added TBAF (1M in THF, 8.6 mL) and the mixture was heated at 75° C. for 2 h. Upon cooling, the mixture was partitioned between EtOAc and 0.2N HCl. The organic phase was washed with 0.2N HCl and sat'd brine. The combined aqueous phases were reextracted with EtOAc. The second EtOAc phase was washed with 0.2N HCl and sat'd brine. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc-hexanes gradient) to afford the title compound as a light yellow solid (0.595 g, 92% yield): 1H NMR (400 MHz, CD3OD) δ 7.53 (d, J=8.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.03 (t, J=54.2 Hz, 1H), 6.95 (bt, J=2 Hz, 1H); MS (ES) m/z 227 (M+1).

Workup

temperatureUpon cooling
customthe mixture was partitioned between EtOAc and 0.2N HCl
washThe organic phase was washed with 0.2N HCl
washThe second EtOAc phase was washed with 0.2N HCl
dry with materialThe combined organic phases were dried (Na2SO4)
concentrationconcentrated in vacuo
customThe residue was purified by flash chromatography (0-50% EtOAc-hexanes gradient)

Sources & evidence

ORD record: ord-9ab8220c83d44b7680db1f2590ce1221
Source dataset: uspto-grants-2014_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08673948B2

Reaction notes

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