tert-Butyl 4-oxopiperidine-1-carboxylate → tert-Butyl4-hydroxy-4-[4-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxylate

HRID 1044584Notes

Reaction equation

Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>C(Cl)Cl>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C:18]([OH:17])([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]

Participants

Conditions

Temperature: -78 °C

Procedure

To a slightly cloudy solution of 2-bromo-4-(trifluoromethyl)pyridine (4.0 g, 14.2 mmol) in dry methylene chloride (52.7 mL) cooled at −78° C. was added a 1.6 M solution of n-butyllithium in hexanes (9.65 mL). After being stirred for 40 min at −78° C., a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (2.59 g, 12.9 mmol) in dry methylene chloride (10.0 mL) was added dropwise. The reaction was stirred at −78° C. for 1 h and quenched with aqueous NH4Cl. THF was removed by rotary evaporation. The aqueous layer was extracted with methylene chloride three times. The combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (30:70 EtOAc/hexanes) to give 2.63 g (59%) of desired product as a brown oil. LC-MS calculated for C16H21F3N2O3: (M+H) 347; found 247.0 (M-Boc+1).

Workup

stirringThe reaction was stirred at −78° C. for 1 h
customquenched with aqueous NH4Cl
customTHF was removed by rotary evaporation
extractionThe aqueous layer was extracted with methylene chloride three times
customThe combined organic layers were dried
filtrationfiltered
concentrationconcentrated
customThe residue was purified by column chromatography on silica gel (30:70 EtOAc/hexanes)

Sources & evidence

ORD record: ord-9fd1a2762adf4c179e4a3b629b3d0628
Source dataset: uspto-grants-2013_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08563582B2

Reaction notes

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