Cesium carbonate → 1,1-Dimethylethyl 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylate

HRID 2081030Notes

Reaction equation

HRID 2081030 reaction equation
[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[N:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[CH:21]=[N:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:3]1=[O:14]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27348955-Bromo-2-methoxypyridineHCID 671035641,1-Dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate

Product 1

HCID 671034301,1-Dimethylethyl 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylateYield 44.3%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.998 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 5-bromo-2-(methyloxy)pyridine (0.259 ml, 1.998 mmol) in 1,4-dioxane (20 ml) was added cesium carbonate (2604 mg, 7.99 mmol), Xantphos™ (87 mg, 0.150 mmol) and tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.100 mmol) and the reaction was stirred at reflux overnight. After cooling the solvent was removed under vacuum and the residue was partitioned between dichloromethane and water. The organic layer was separated, washed with saturated sodium hydrogen carbonate solution, water and then brine and passed through a hydrophobic frit. The organic layer was reduced under vacuum and the residue was purified by Flashmaster automated silica gel chromatography eluting with 0-30% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylate (272 mg, 43.4% yield). LC/MS [M+H]+=308. (ii) Trifluoroacetic acid (1 ml) was added to a solution of 1,1-dimethylethyl 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylate (270 mg, 0.878 mmol) in dichloromethane (2 ml) and the solution was stirred at room temperature overnight. The reaction mixture reduced to dryness under vacuum azeotroping with toluene and then dried under heated vacuum overnight to give 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜0.88 mmol). LC/MS [M+H]+=252.

Workup

  1. temperatureat reflux overnight
  2. temperatureAfter cooling the solvent
  3. customwas removed under vacuum
  4. customthe residue was partitioned between dichloromethane and water
  5. customThe organic layer was separated
  6. washwashed with saturated sodium hydrogen carbonate solution, water
  7. customthe residue was purified by Flashmaster automated silica gel chromatography
  8. washeluting with 0-30% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-9c84bf81133640c08b563d528d232ab5
Source dataset
uspto-grants-2011_04
Patent number
US07932282B2

Reaction notes

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