m-Formylbenzonitrile → 3-[(5-Ethyl-6-methoxy-2-methylpyridin3-yl)hydroxymethyl]benzonitrile

HRID 1921339Notes

Reaction equation

C([Li])CCC.Br[C:7]1[C:8]([CH3:17])=[N:9][C:10]([O:15][CH3:16])=[C:11]([CH2:13][CH3:14])[CH:12]=1.[C:18]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24])#[N:19]>O1CCCC1>[CH2:13]([C:11]1[CH:12]=[C:7]([CH:23]([OH:24])[C:22]2[CH:21]=[C:20]([CH:27]=[CH:26][CH:25]=2)[C:18]#[N:19])[C:8]([CH3:17])=[N:9][C:10]=1[O:15][CH3:16])[CH3:14]

Participants

Conditions

Temperature: -50 °C

Procedure

Butyl lithium (2.5M in hexane, 2.09 mL, 5.22 mmol) is added to a solution of 3-bromo-5-ethyl-6-methoxy-2-methylpyridine (1.0 g, 4.35 mmol) in tetrahydrofuran (10 mL) cooled to −50° C. and the reaction mixture is stirred for 45 min after which 3-cyanobenzaldehyde (0.71 g, 5.44 mmol) is added in two portions. After 1 hr at −50° C., the dry ice/acetone bath is removed, the reaction is warmed to room temperature, quenched with sat. aq ammonium chloride (30 mL) and extracted with ether (40 mL). The extract is dried, filtered, concentrated and the residue is purified by chromatography eluting with cyclohexane and 10 to 15% ethyl acetate. Product containing fractions are combined and concentrated to afford 3-[(5-ethyl-6-methoxy-2-methylpyridin3-yl)hydroxymethyl]benzonitrile (0.69 g, 56% yield).

Workup

additionis added in two portions
customthe dry ice/acetone bath is removed
temperaturethe reaction is warmed to room temperature
customquenched with sat. aq ammonium chloride (30 mL)
extractionextracted with ether (40 mL)
customThe extract is dried
filtrationfiltered
concentrationconcentrated
customthe residue is purified by chromatography
washeluting with cyclohexane and 10 to 15% ethyl acetate
additionProduct containing fractions
concentrationconcentrated

Sources & evidence

ORD record: ord-ed6eb99d0c0d488c9bac9af35827fd93
Source dataset: uspto-grants-2012_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08173682B2

Reaction notes

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