Lithium diisopropylamide → 2-(4-Benzyloxy-phenyl)-3-cyclopentyl-propionic acid methyl ester

HRID 1935219Notes

Reaction equation

HRID 1935219 reaction equation
C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:27])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:15][CH:14]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1

Participants

6

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 2756645Methyl 2-(4-benzyloxyphenyl)acetateHCID 2762531(Iodomethyl)cyclopentane

Product 1

HCID 674831552-(4-Benzyloxy-phenyl)-3-cyclopentyl-propionic acid methyl esterYield 86.6%

Reagents, catalysts & solvents 2

HCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-SolventHCID 22565281tetrahydrofuran 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinoneSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) was cooled to −78° C. and then treated with a solution of (4-benzyloxy-phenyl)-acetic acid methyl ester (1.66 g, 6.48 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 g, 7.13 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. At this time, the reaction mixture was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate) afforded 2-(4-benzyloxy-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.90 g, 86.6%) as a white wax: mp 55-57° C.; EI-HRMS m/e calcd for C22H26O3 (M+) 338.1881 found 228.1878.

Workup

  1. stirringThe reaction mixture was stirred at −78° C. for 4 h
  2. temperatureThe reaction was then warmed to 25° C.
  3. stirringwas stirred at 25° C. for 48 h
  4. customAt this time, the reaction mixture was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL)
  5. additionThis mixture was poured into water (100 mL)
  6. extractionextracted with ethyl acetate (3×50 mL)
  7. washThe combined organic extracts were washed with a saturated aqueous lithium chloride solution (1×100 mL)
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-8de072cbbe9d494aad82c282f889d913
Source dataset
uspto-grants-2002_05
Patent number
US06384220B2

Reaction notes

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