Potassium Carbonate → tert-butyl 5,7-dichloro-2-(4-methoxybenzyl)-3-oxo-2',3'-dihydro-1'H-spiro[isoindoline-1,4'-pyridine]-1'-carboxylate

HRID 390141Notes

Reaction equation

HRID 390141 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([N:14]([C:24](=[O:34])[C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[C:26]=2I)[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:32][C:27]1[CH:26]=[C:25]2[C:30](=[C:29]([Cl:31])[CH:28]=1)[C:11]1([CH:12]=[CH:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[N:14]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:24]2=[O:34]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 11776TriphenylphosphineHCID 582957824-[(3,5-Dichloro-2-iodo-benzoyl)-(4-methoxy-benzyl)-amino]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

Product 1

HCID 58295806tert-butyl 5,7-dichloro-2-(4-methoxybenzyl)-3-oxo-2',3'-dihydro-1'H-spiro[isoindoline-1,4'-pyridine]-1'-carboxylateYield 48%

Reagents, catalysts & solvents 3

HCID 74236Tetrabutylammonium BromideCatalystHCID 167845palladium(II) acetateCatalystHCID 6342AcetonitrileSolvent

Procedure

4-[(3,5-Dichloro-2-iodo-benzoyl)-(4-methoxy-benzyl)-amino]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (9.0 g, 15 mmol) was dissolved in 100 mL of acetonitrile in a three flask fitted with a condenser and the mixture was sparged with N2 for 1 h. The flask was quickly opened and Pd(OAc)2 (336 mg, 1.5 mmol), PPh3 (786 mg, 3.0 mmol), K2CO3 (4.14 g, 30 mmol) and nBu4NBr (4.82 g, 15 mmol) was added. The mixture was heated to reflux overnight. After this time, the iodide was consumed and the mixture was cooled to rt and evaporated. The residue was taken up with EtOAc/H2O and the layers were separated. The organic layer was washed with brine, dried and concentrated to give the crude product. It was purified by column chromatography (PE:EtOAc=10:1) to give tert-butyl 5,7-dichloro-2-(4-methoxybenzyl)-3-oxo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridine]-1′-carboxylate (3.5 g, 48%). 1H NMR (CDCl3): 1.52 (s, 9H), 1.63 (s, 1H), 1.78 (m, 1H), 2.71 (m, 1H), 3.04 (m, 1H), 3.78 (s, 3H), 3.97 (m, 1H), 4.25 (m, 1H), 4.46 (m, 1H), 5.02 (m, 1H), 6.82 (m, 2H), 7.18 (m, 2H), 7.52 (s, 1H), 7.81 (s, 1H).

Workup

  1. customfitted with a condenser
  2. customthe mixture was sparged with N2 for 1 h
  3. temperatureThe mixture was heated
  4. temperatureto reflux overnight
  5. customAfter this time, the iodide was consumed
  6. customevaporated
  7. customthe layers were separated
  8. washThe organic layer was washed with brine
  9. customdried
  10. concentrationconcentrated
  11. customto give the crude product
  12. customIt was purified by column chromatography (PE:EtOAc=10:1)

Sources & evidence

ORD record
ord-960480494c0c44d4a03db1227b21edc6
Source dataset
uspto-grants-2013_02
Patent number
US08383629B2

Reaction notes

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