1-Benzyl-4-piperidone → 1-Benzyl-4-[4-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine

HRID 1727045Notes

Reaction equation

HRID 1727045 reaction equation
I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Li]CCCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O1CCOCC1>[CH2:17]([N:24]1[CH2:25][CH:26]=[C:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH2:28][CH2:29]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1

Participants

8

Reactant 4

HCID 192201-Benzyl-4-piperidoneHCID 67993Benzene, 1-iodo-4-(trifluoromethyl)-HCID 516892Sodium BicarbonateHCID 178418339Butyllithium

Product 1

HCID 161275071-Benzyl-4-[4-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridineYield 28.3%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 8028TetrahydrofuranSolvent3×HCID 312751,4-DioxaneSolvent

Procedure

4-Iodobenzo trifluoride (2.97 g, 10.92 mmol) in THF (50 mL) was added dropwise over 0.5 h to a solution of n-BuLi (7.5 ml, 1.6 M, 12 mmol) in THF (50 mL) at −78° C. The reaction mixture was stirred an additional 0.5 h upon which N-benzyl-4-piperidone (2.13 g, 11.69 mmol) in THF (10 mL) was added over 10 minutes. Stirring was continued for 0.5 h at −78° C., followed by room temperature overnight. The reaction was quenched with saturated ammonium chloride and the organic layer was separated. The aqueous layer was extracted with THF and the combined organic layers were dried (MgSO4), filtered and concentrated to afford a brown oil. The crude product was then dissolved in conc. HCl (30 mL) and 1,4-dioxane (6 mL) and stirred at 100° C. overnight. The reaction was poured into saturated sodium bicarbonate and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The product was purified by silica gel flash column chromatography (20% ethyl acetate in hexanes) to afford 1-benzyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (981 mg, 28%). 1H NMR (400 MHz, CDCl3) 7.61 (d, 2H), 7.52 (d, 2H), 7.40 (m, 5H), 6.21 (m, 1H), 3.70 (s, 2H), 3.25 (q, 2H), 2.78 (t, 2H), 2.62 (m, 2H); LCMS: 318.4 (M+1)+.

Workup

  1. additionwas added over 10 minutes
  2. waitfollowed by room temperature overnight
  3. customThe reaction was quenched with saturated ammonium chloride
  4. customthe organic layer was separated
  5. extractionThe aqueous layer was extracted with THF
  6. dry with materialthe combined organic layers were dried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto afford a brown oil
  10. extractionextracted with ethyl acetate (3×200 mL)
  11. dry with materialThe combined organic layers were dried (MgSO4)
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe product was purified by silica gel flash column chromatography (20% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-80718892465f4b6685838ebdfc3a1b93
Source dataset
uspto-grants-2009_02
Patent number
US07494999B2

Reaction notes

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