Acetic Acid → 3,3-Difluoro-1'-[3-(methyloxy)-4-nitrophenyl]-1,4'-bipiperidine

HRID 1014196Notes

Reaction equation

HRID 1014196 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].Cl.[F:20][C:21]1([F:27])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C(O)(=O)C.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:20][C:21]1([F:27])[CH2:26][CH2:25][CH2:24][N:23]([CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:22]1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 8471TriethylamineHCID 27583493,3-Difluoropiperidine hydrochlorideHCID 5049666Sodium triacetoxyborohydrideHCID 259188571-(3-Methoxy-4-nitrophenyl)piperidin-4-one

Product 1

HCID 594418643,3-Difluoro-1'-[3-(methyloxy)-4-nitrophenyl]-1,4'-bipiperidineYield 68.5%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

A mixture of 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (600 mg, 2.4 mmol), commercially available 3,3-difluoropiperidine hydrochloride (753 mg, 4.8 mmol), acetic acid (0.20 mL, 3.6 mmol) and triethylamine (0.33 mL, 3.6 mmol) in 1,2-dichloroethane was stirred for 30 minutes. Sodium triacetoxyborohydride (615 mg, 2.9 mmol) was added. When LC/MS indicated the absence of starting material, the reaction was quenched with the addition of sat'd NaHCO3. The reaction was diluted with dichloromethane and the layers were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with water, dried over MgSO4 and concentrated onto silica gel. The crude material was purified by flash column chromatography to give 3,3-difluoro-1′-[3-(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine (584 mg, 68%). 1H NMR (400 MHz, d6-DMSO) δ 7.84 (d, J=9.6 Hz, 1H), 6.55 (dd, J=9.6 and 2.0 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 4.04 (d, J=12.8 Hz, 1H), 3.87 (s, 3H), 2.90 (t, J=12.0 Hz, 2H), 2.72-2.60 (m, 3H), 2.47 (m under DMSO peak, 2H), 1.87-1.74 (m, 4H), 1.61-1.58 (m, 2H), 1.48-1.38 (m, 2H).

Workup

  1. customthe reaction was quenched with the addition of sat'd NaHCO3
  2. additionThe reaction was diluted with dichloromethane
  3. customthe layers were separated
  4. extractionThe aqueous phase was extracted with dichloromethane
  5. washThe combined organic layers were washed with water
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated onto silica gel
  8. customThe crude material was purified by flash column chromatography

Sources & evidence

ORD record
ord-f1ec5a868291443386da27751e178fc3
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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