Propionitrile → Methyl 6-[(1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate

HRID 633929Notes

Reaction equation

HRID 633929 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.C(#N)CC.CCN(C(C)C)C(C)C.[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:35]([O:34][C:30](=[O:33])/[CH:31]=[CH:32]/[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([C:13]([O:15][CH3:16])=[O:14])[CH2:5]2)([CH3:38])([CH3:37])[CH3:36]

Participants

8

Reactant 5

HCID 7854PropionitrileHCID 15458tert-Butyl acrylateHCID 80271Tri-o-tolylphosphine2×HCID 81531DiisopropylethylamineHCID 11108881Methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate

Product 1

HCID 68338025Methyl 6-[(1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylateYield 32.6%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a suspension of methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (300 mg, 1.06 mmol), prepared as in J. Med. Chem. 2003, 46, 9, 1627-1635, in DMF (1 mL) and proprionitrile (3.5 mL) under Argon were added DIPEA (175 μL, 2.271 mmol), tert-butyl acrylate (615 mL, 4.24 mmol), tri(o-tolyl)phosphine (64 mg, 0.21 mmol) and palladium acetate (48 mg, 0.21 mmol). The mixture was stirred at 100° C. overnight. LCMS analysis showed that some unreacted starting material was remaining, so 24 mg of palladium acetate and 64 mg of tri(o-tolyl)phosphine were added. After 5 h at 100° C., the reaction was allowed to come back to room temperature, filtered through Celite pad and rinsed with methanol. The residue obtained after concentration was purified by flash chromatography (eluent: gradient DCM/EtOAc) to give the title compound as an orange solid (115 mg, 32%) contaminated with traces of tri(o-tolyl)phosphine oxide.

Workup

  1. waitAfter 5 h at 100° C.
  2. customto come back to room temperature
  3. filtrationfiltered through Celite pad
  4. washrinsed with methanol
  5. customThe residue obtained
  6. concentrationafter concentration
  7. customwas purified by flash chromatography (eluent: gradient DCM/EtOAc)

Sources & evidence

ORD record
ord-e5359a9a87cb4f5f9c794c46d3315bc8
Source dataset
uspto-grants-2016_04
Patent number
US09321769B2

Reaction notes

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