N-methyl-2-pyrrolidone → 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile

HRID 1188426Notes

Reaction equation

[CH3:1][N:2]1C(=O)CCC1.Cl[C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)C(C)(C)C)=[C:11]([C:22]#[C:23][CH3:24])[C:10]=1[C:25]([F:28])([F:27])[F:26].C([Cu])#N.[OH-].[NH4+]>CCOCC>[CH3:24][C:23]1[NH:15][C:12]2[C:11]([CH:22]=1)=[C:10]([C:25]([F:26])([F:27])[F:28])[C:9]([C:1]#[N:2])=[CH:14][CH:13]=2

Participants

Conditions

Temperature: 195 °C

Procedure

An NMP solution (150 mL) of N-[4-chloro-2-(1-propyn-1-yl)-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (10 g, 31.5 mmol) was treated with CuCN (11.3 g, 126 mmol) and the resulting mixture was heated at 195° C. for 90 h. Two reactions were carried out simultaneously. The combined dark brown reaction mixture was poured into crushed ice (250 mL) containing conc. ammonium hydroxide (100 mL). The resulting slurry was stirred with the addition of Et2O and filtered through celite. The filtrate was diluted with Et2O and partitioned. The aqueous portion was extracted with Et2O four times. The combined organic portions were washed with brine and dried (MgSO4). Filtration and concentration in vacuo followed by radial chromatography (SiO2, 0-60% EtOAc-hexanes gradient) afforded the title compound as a solid (9 g, 64%):

Workup

additionThe combined dark brown reaction mixture was poured
filtrationfiltered through celite
additionThe filtrate was diluted with Et2O
custompartitioned
extractionThe aqueous portion was extracted with Et2O four times
washThe combined organic portions were washed with brine
dry with materialdried (MgSO4)
filtrationFiltration and concentration in vacuo

Sources & evidence

ORD record: ord-39496a3b41044eaea452c81f16c972eb
Source dataset: uspto-grants-2014_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08673948B2

Reaction notes

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