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

HRID 2080984Notes

Reaction equation

HRID 2080984 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[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=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.O.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[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[C:3]1=[O:14]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 2208322-Bromo-3-methylpyridineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 671035641,1-Dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate

Product 1

HCID 671035671,1-Dimethylethyl 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylateYield 80.1%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-bromo-3-methylpyridine (515 mg, 3 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.5 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (700 mg, 80%). LC/MS [M+H]+=292. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (700 mg, 2.4 mmol) in TFA/DCM (1:2, 12 ml) was stirred at room temperature for 6 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜2.4 mmol) which was used in the next step. LC/MS [M+H]+=236.

Workup

  1. temperaturethe mixture was heated
  2. temperatureunder reflux under argon for 18 hours
  3. extractionextracted with ethyl acetate
  4. washwashed with water and brine
  5. customevaporated in vacuo
  6. customThe residue was purified by silica gel chromatography
  7. washeluting with 0-100% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-b5656e1b32144431b74004b135b66b8e
Source dataset
uspto-grants-2011_04
Patent number
US07932282B2

Reaction notes

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