4-Methylquinoline → 2-(1-Fluorocyclopropyl)-4-(4-fluorophenyl)-4-methyl-1-quinolin-4-ylpentan-2-ol

HRID 400686Notes

Reaction equation

[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Li].[F:13][C:14]1([C:17](=[O:29])[CH2:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([CH3:21])[CH3:20])[CH2:16][CH2:15]1>C1COCC1>[F:13][C:14]1([C:17]([OH:29])([CH2:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)([CH3:21])[CH3:20])[CH2:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:15][CH2:16]1

Participants

Conditions

Temperature: -78 °C

Procedure

To a solution of 4-methylquinoline (69 mg, 0.482 mmol) in THF cooled on dry ice/acetone was added 0.4 mL of lithium dilsopropylamide (1.5 M in hexanes). The mixture was placed in a cold bath at −20° C. to −30° C. for 15 minutes and then cooled to −78° C. 1-(1-Fluorocyclopropyl)-3-(4-fluorophenyl)-3-methylbutan-1-one (49 mg, 0.206 mmol) was added dropwise as a solution in 0.5 mL of THF. The cold bath was then removed and the mixture stirred for 1 hour. The reaction was quenched by addition of 0.5 mL of water and diluted with ethyl acetate. The organic phase was separated, washed with water, dried, filtered, and the solvent evaporated in vacuo. Fractionation of the residue by preparative layer chromatography (developer: ethyl acetate-hexanes (2:1)) gave the title compound (0.019 g, 24% yield) (slightly less polar than lepidine) as an oil that crystallized on standing in hexanes, m.p. 152° C.-155° C.

Workup

customThe cold bath was then removed
customThe reaction was quenched by addition of 0.5 mL of water
additiondiluted with ethyl acetate
customThe organic phase was separated
washwashed with water
customdried
filtrationfiltered
customthe solvent evaporated in vacuo

Sources & evidence

ORD record: ord-7f0814b7367e4ca19d7aeaa04d8b85f1
Source dataset: uspto-grants-2014_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08741897B2

Reaction notes

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