2-(4-Chlorophenoxy)aniline → 1-(3-(1-(2-(4-Chlorophenoxy)phenylamino)ethyl)phenyl)pyrrolidin-2-one

HRID 1043034

Reaction equation

HRID 1043034 reaction equation
[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])=[CH:4][CH:3]=1.C(N1CC[CH:22]([C:25]([N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=O)[CH3:37])[CH:31]=2)[CH2:28][CH3:29])=[O:26])CC1)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].C(O[Ti+](OC(C)C)OC(C)C)(C)C.O.CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9][CH:36]([C:32]2[CH:31]=[C:30]([N:27]3[CH2:28][CH2:29][CH2:22][C:25]3=[O:26])[CH:35]=[CH:34][CH:33]=2)[CH3:37])=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 760102-(4-Chlorophenoxy)anilineHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 684308061-acetyl-N-(3-acetylphenyl)-N-ethylpiperidine-4-carboxamide

Product 1

HCID 426136711-(3-(1-(2-(4-Chlorophenoxy)phenylamino)ethyl)phenyl)pyrrolidin-2-one

Reagents, catalysts & solvents 4

HCID 3084342Chlorotitanium triisopropoxideCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

2-(4-Chlorophenoxy)aniline (245 mg, 1.118 mmol, 1 eq) and 1-acetyl-N-(3-acetylphenyl)-N-ethylpiperidine-4-carboxamide (250 mg, 1.230 mmol, 1.1 eq) were stirred in dry dichloromethane (DCM) (2 mL) at room temperature for 10 min. Tri-isopropoxytitanium chloride (534 μL, 2.236 mmol, 2 eq) was added to the reaction mixture which was stirred at room temperature for 16 hours. Sodium triacetoxyborohydride (947 mg, 4.472 mmol, 4 eq) was then added to the reaction mixture and was stirred at room temperature for a further 24 h. The reaction mixture was then poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (120 mL). The organic layer was washed with brine (120 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [0-10% MeOH/DCM] gave (437 mg, 91%) as a pale yellow oil. 1H NMR (270 MHz, CDCl3) δ 1.45 (3H, d, J=8.1 Hz, CH3), 2.02-2.18 (2H, m, CH2), 2.58 (2H, t, J=10.8 Hz, CH2), 3.77 (2H, t, J=9.7 Hz, CH2), 4.50 (2H, m, NH and CH), 6.47-6.62 (2H, m, Ar) 6.77-6.96 (4H, m, Ar), 7.09 (1H, d, J=8.1 Hz, Ar), 7.22-7.32 (3H, m, Ar), 7.48 (1H, dd, J=2.4, 8.1 Hz, Ar), 7.59 (1H, m, Ar). LCMS (90% MeOH and 10% H2O; Symmetry C18 reverse phase column) tr=2.73 min; (ES+), m/z 407.2. HPLC 98.56% purity.

Workup

  1. stirringwas stirred at room temperature for a further 24 h
  2. extractionextracted with DCM (120 mL)
  3. washThe organic layer was washed with brine (120 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give the crude as a yellow oil
  8. customPurification of the crude by flash chromatography (ISCO)
  9. washeluting with a gradient [0-10% MeOH/DCM]
  10. customgave (437 mg, 91%) as a pale yellow oil

Sources & evidence

ORD record
ord-15968998e74547b8b556e163b605c460
Source dataset
uspto-grants-2013_10
Patent number
US08558028B2

Linked notes

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