4,4-Difluorocyclohexanone → 2-(4,4-Difluorocyclohexylidene)-2-(2-methylpyrimidin-5-yl)acetonitrile

HRID 512178Notes

Reaction equation

[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][N:3]=1.[F:11][C:12]1([F:19])[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.CC([O-])(C)C.[K+]>O1CCOCC1>[F:11][C:12]1([F:19])[CH2:17][CH2:16][C:15](=[C:8]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=2)[C:9]#[N:10])[CH2:14][CH2:13]1

Participants

Conditions

Temperature: 60 °C

Procedure

To a solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (1 g, 7.52 mmol) and 4,4-difluorocyclohexanone (1.1 g, 8.27 mmol) in 1,4-dioxane (40 mL) was added t-BuOK (0.8 g, 8.27 mmol) in two portions. After the addition was completed, the reaction was heated to 60° C. and stirred overnight. The reaction solution was cooled to 0° C., quenched by saturated NH4Cl aq. solution and extracted with EtOAC (50 m×3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to get the crude product, which was purified by column chromatography on silica gel (Petroleum ether: EtOAc=4:1˜2:1) to afford 2-(4,4-difluorocyclohexylidene)-2-(2-methylpyrimidin-5-yl)acetonitrile (440 mg, yield: 23.5%). 1H NMR (CDCl3 varian 400 MHz): δ8.61 (s, 2H), 2.97 (t, J=8.0 Hz, 2H), 2.80 (s, 3H), 2.55 (t, J=8.0 Hz, 2H), 2.27-2.17 (m, 2H), 2.09-1.98 (m, 2H).

Workup

additionAfter the addition
temperatureThe reaction solution was cooled to 0° C.
customquenched by saturated NH4Cl aq. solution
extractionextracted with EtOAC (50 m×3)
washThe combined organic layer was washed with brine
dry with materialdried over Na2SO4
concentrationconcentrated
customto get the crude product, which
customwas purified by column chromatography on silica gel (Petroleum ether: EtOAc=4:1˜2:1)

Sources & evidence

ORD record: ord-42bdd4d448c743ecabcc1528721275cc
Source dataset: uspto-grants-2015_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09102591B2

Reaction notes

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