Cesium carbonate → 5-Morpholin-4-yl-1-[4-(2-oxopiperidin-1-yl)phenyl]-2,3-dihydropyridin-6-one

HRID 896815Notes

Reaction equation

HRID 896815 reaction equation
I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:9]2=[O:20])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu+]>[N:14]1([C:10]2[C:9](=[O:20])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=[O:27])=[CH:3][CH:4]=3)[CH2:13][CH2:12][CH:11]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 126652-PiperidoneHCID 222404531-(4-Iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one

Product 1

HCID 223522265-Morpholin-4-yl-1-[4-(2-oxopiperidin-1-yl)phenyl]-2,3-dihydropyridin-6-oneYield 77%

Reagents, catalysts & solvents 2

HCID 104815Copper(1+)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
7.5 °C

Procedure

Part B. Soluble copper(I)-catalyzed Ullmann coupling reaction. A suspension of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (10, 2.2 g, 5.73 mmol), piperidin-2-one (42, 851 mg, 8.59 mmol, 1.5 equiv), and Cs2CO3 (3.73 g, 11.46 mmol, 2.0 equiv) in toluene (15 mL) was treated with Cu(PPh3)3Br (1.065 g, 1.146 mmol, 20% equiv) at room temperature under N2, and the resulting reaction mixture was degassed three times under a steady stream of nitrogen. The reaction mixture was warmed up to reflux for 6 h. When HPLC showed the Ullmann coupling reaction was complete, the reaction mixture was cooled down to 5-10° C. before being quenched with 14% of ammonium hydroxide aqueous solution (20 mL) and EtOAc (30 mL) at 5-10° C. The mixture was stirred for an additional 4 h at 25° C. The two layers were then separated, and the aqueous layer, was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-5,6-dihydro-1H-pyridin-2-one (63, 1.568 g, 2.036 g theoretical, 77%) as a pale-yellow oil, which solidified upon standing at room temperature in vacuo. For 63, CIMS m/z 356 (M++H, C2OH25N3O3).

Workup

  1. customreaction
  2. customthe resulting reaction mixture
  3. customwas degassed three times under a steady stream of nitrogen
  4. temperatureThe reaction mixture was warmed up
  5. temperatureto reflux for 6 h
  6. customthe Ullmann coupling reaction
  7. custombefore being quenched with 14% of ammonium hydroxide aqueous solution (20 mL) and EtOAc (30 mL) at 5-10° C
  8. customThe two layers were then separated
  9. extractionthe aqueous layer, was extracted with EtOAc (3×20 mL)
  10. washThe combined organic extracts were washed with saturated NaCl aqueous solution (10 mL)
  11. dry with materialdried over MgSO4
  12. concentrationconcentrated in vacuo
  13. customThe residue was directly purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution)

Sources & evidence

ORD record
ord-d5222448f8114b1d901ed78006a97620
Source dataset
uspto-grants-2005_07
Patent number
US06919451B2

Reaction notes

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