p-Bromochlorobenzene → tert-Butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate

HRID 521358Notes

Reaction equation

HRID 521358 reaction equation
C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[C:14]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C1C[O:31]CC1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]2([OH:31])[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22][CH2:23]2)=[CH:8][CH:9]=1

Participants

5

Reactant 4

HCID 7806p-BromochlorobenzeneHCID 8028Tetrahydrofuran2×HCID 7577838tert-Butyl 2-oxopiperidine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 21997555tert-Butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylateYield 74%

Procedure

n-Butyl lithium (16 mL, 2.5M solution in hexanes, 39.9 mmol) was added to a solution of 1-bromo-4-chlorobenzene (8.62 g, 45.0 mmol) in anhydrous THF (100 mL) at −78° C. under nitrogen. After 30 minutes at −78° C., 1-Boc-piperidone (6.62 g, 33.2 mmol) was added dropwise as a solution in anhydrous THF (5 mL). After 30 minutes at −78° C., the reaction was quenched with a saturated NH4Cl solution (100 mL), extracted with EtOAc (2×100 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with EtOAc/hexane (0-40%) to give tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (7.64 g, 74% yield). 1H NMR (CDCl3, 400 MHz) δ 7.38 (d, J=7.2 Hz, 2H), 7.15 (d, J=7.3 Hz, 2H), 3.94 (br s, 2H), 3.18 (br s, 2H), 1.89 (br s, 2H), 1.46 (s, 11H). LCMS: M+1 312.2.

Workup

  1. waitAfter 30 minutes at −78° C.
  2. customthe reaction was quenched with a saturated NH4Cl solution (100 mL)
  3. extractionextracted with EtOAc (2×100 mL)
  4. dry with materialThe combined organics were dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product was purified by silica gel chromatography
  8. washeluting with EtOAc/hexane (0-40%)

Sources & evidence

ORD record
ord-6647d9e849174232bb75c0551bdef77c
Source dataset
uspto-grants-2016_05
Patent number
US09328091B2

Reaction notes

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