(4-Chlorophenyl)acetic acid → 2-(4-Chloro-phenyl)-3-cyclopentyl-propionic acid

HRID 398465Notes

Reaction equation

HRID 398465 reaction equation
C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.I[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1

Participants

6

Reactant 3

HCID 15880(4-Chlorophenyl)acetic acidHCID 2724682Lithium diisopropylamideHCID 2762531(Iodomethyl)cyclopentane

Product 1

HCID 223152972-(4-Chloro-phenyl)-3-cyclopentyl-propionic acidYield 79.1%

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 (78.0 mL of a 0.91M stock solution, 70.98 mmol) cooled to −78° C. was treated with (4-chloro-phenyl)-acetic acid (5.76 g, 33.8 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (84 mL, 3:1). The resulting solution was stirred at −78° C. for 1 h. Iodomethylcyclopentane (7.45 g, 35.49 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). This solution was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. The mixture was then poured into water (150 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid (6.76 g, 79.1%) as a yellow solid: mp 82-84° C.: EI-HRMS m/e calcd for C14H17ClO2 (M+) 252.0917, found 252.0906.

Workup

  1. stirringThis solution was stirred at −78° C. for 4 h
  2. temperatureThe reaction was then warmed to 25° C.
  3. stirringwas stirred at 25° C. for 16 h
  4. customThe reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL)
  5. customThe excess solvent was removed in vacuo
  6. additionThe mixture was then poured into water (150 mL)
  7. extractionextracted with ethyl acetate (3×50 mL)
  8. dry with materialThe combined organic layers were dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-ba4df412b035424d8af3acfb2593e916
Source dataset
uspto-grants-2003_08
Patent number
US06610846B1

Reaction notes

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