3-Bromobenzonitrile → 1,1-Dimethylethyl 4-(3-cyanophenyl)-4-hydroxy-1-piperidinecarboxylate

HRID 489607Notes

Reaction equation

HRID 489607 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Li]CCCC.[C:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C1COCC1>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][C:25]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)([OH:28])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]

Participants

5

Reactant 3

HCID 233813-BromobenzonitrileHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 222661661,1-Dimethylethyl 4-(3-cyanophenyl)-4-hydroxy-1-piperidinecarboxylateYield 37.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-15 °C

Procedure

A solution of 3-Bromobenzonitrile (0.48 g, 2.64 mmol) in THF (20 mL) was stirred under nitrogen at −78° C. To this was added dropwise a solution of 2.0M nBuLi in hexanes (1.38 mL, 2.72 mmol). The solution was allowed to warm to −15° C. over 1.5 hours. The solution was recooled to −78° C. and a solution of N-Boc-4-piperidone (0.53 g, 2.64 mmol) in THF (5 mL) was added dropwise. The reaction mixture was allowed to warm to −10° C. and stirred at this temperature for three hours. The reaction was quenched with ½ saturated ammonium chloride solution (30 mL) and stirred 15 minutes. The THF was removed by evaporation and the residue extracted with methylene chloride (3×50 mL). The organic extracts were combined, dried over sodium sulfate, evaporated to give an orange oil which was purified by flash chromatography 3:5:2 methylene chloride: heptane: ethyl acetate to give the title compound (0.30 g) as a clear oil. 1H NMR [(CDCl3]: δ 7.82 (s, 1H), 7.72 (d, 1H), 7.58 (d, 1H), 7.55-7.42 (m, 1H), 4.20-3.95 (m, 2H), 3.35-3.10 (m, 2H), 2.08-1.83 (m, 2H), 1.80-1.66 (m, 2H), 1.51 (s, 9H).

Workup

  1. customwas recooled to −78° C.
  2. temperatureto warm to −10° C.
  3. customThe reaction was quenched with ½ saturated ammonium chloride solution (30 mL)
  4. stirringstirred 15 minutes
  5. customThe THF was removed by evaporation
  6. extractionthe residue extracted with methylene chloride (3×50 mL)
  7. dry with materialdried over sodium sulfate
  8. customevaporated
  9. customto give an orange oil which
  10. customwas purified by flash chromatography 3:5:2 methylene chloride

Sources & evidence

ORD record
ord-760daa543e574c46845e0225345f1cea
Source dataset
uspto-grants-2005_12
Patent number
US06977263B2

Reaction notes

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