Lithium diisopropylamide → 3-(2-Methylsulfanyl-pyrimidin-4-yl)-3-oxo-2-ortho-tolyloxy-propionic acid methyl ester

HRID 1455239Notes

Reaction equation

HRID 1455239 reaction equation
C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:22])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])C.CON(C)[C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=1)=[O:27]>C1COCC1>[CH3:9][O:11][C:12](=[O:22])[CH:13]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=1)=[O:27]

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 3022879Ethyl 2-(2-methylphenoxy)acetateHCID 21948429N-methoxy-N-methyl-2-(methylthio)pyrimidine-4-carboxamide

Product 1

HCID 575317893-(2-Methylsulfanyl-pyrimidin-4-yl)-3-oxo-2-ortho-tolyloxy-propionic acid methyl esterYield 32%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

To a cold (−78° C.) solution of lithium diisopropylamide (31.5 mL of 1.8 M solution in THF, 56.6 mmol) in THF (180 mL) is added dropwise a solution of ethyl-(2-methylphenoxy)acetate (10.0 g, 51.5 mmol) in THF (30 mL). After stirring for 1 h at −78° C. a solution of 2-methylsulfanyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide (10.4 g, 48.9 mmol) in THF (30 mL) is added dropwise to the reaction mixture. After stirring 20 min at −78° C., the reaction mixture is warmed to 0° C. and stirred for an additional 30 min. The reaction is quenched by pouring into aqueous saturated NH4Cl. The aqueous phase is extracted with EtOAc (×2). The combined organic phases are dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified by silica gel chromatography (10% EtOAc/hexanes, followed by 30% EtOAc/hexanes) to afford 2.1 g (32%) of the desired product. 1H NMR (300 MHz, CDCl3) (observed 3:1 mixture of keto:enol tautomers) keto tautomer: δ 8.80 (d, J=4.2 Hz, 1H), 7.57 (d, J=4.8 Hz, 1H), 7.20-7.14 (m, 2H), 6.96 (t, J=7.2 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.29 (s, 1H), 4.30 (q, J=7.2 Hz, 2H), 2.50 (s, 3H), 2.27 (s, 3H), 1.26 (t, J=7.2 Hz, 3H); ESI+ MS: m/z (rel intensity) 347.1 (100, M++H).

Workup

  1. additionis added dropwise to the reaction mixture
  2. temperaturethe reaction mixture is warmed to 0° C.
  3. stirringstirred for an additional 30 min
  4. customThe reaction is quenched
  5. additionby pouring into aqueous saturated NH4Cl
  6. extractionThe aqueous phase is extracted with EtOAc (×2)
  7. dry with materialThe combined organic phases are dried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe crude residue is purified by silica gel chromatography (10% EtOAc/hexanes, followed by 30% EtOAc/hexanes)

Sources & evidence

ORD record
ord-882bd6f38f09452a893a46362338bcca
Source dataset
uspto-grants-2009_01
Patent number
US07482356B2

Reaction notes

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