(alpha,alpha,alpha-Trifluoro-4-tolyl)acetic acid → 3-Cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid

HRID 1355002Notes

Reaction equation

HRID 1355002 reaction equation
C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH:25]1([CH2:24][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:21])([F:22])[F:9])=[CH:16][CH:15]=2)[C:18]([OH:20])=[O:19])[CH2:29][CH2:28][CH2:27][CH2:26]1

Participants

6

Reactant 3

HCID 118342(alpha,alpha,alpha-Trifluoro-4-tolyl)acetic acidHCID 2724682Lithium diisopropylamideHCID 2762531(Iodomethyl)cyclopentane

Product 1

HCID 223152793-Cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acidYield 65.2%

Reagents, catalysts & solvents 2

HCID 12679HexamethylphosphoramideSolventHCID 86583969tetrahydrofuran HMPASolvent

Conditions

Temperature
-78 °C

Procedure

A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-trifluoromethyl-phenyl)-acetic acid (693 mg, 3.4 mmol) in tetrahydrofuran/hexamethylphosphoramide (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 30 min. Iodomethylcyclopentane (784 mg, 3.7 mmol) was then added in hexamethylphosphoramide (1 mL). The mixture 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 (10 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 (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (634.9 mg, 65%) as a white solid: mp 94–95° C.; EI-HRMS m/e calcd for C15H17F3O2 (M+) 309.1079, found 309.1072.

Workup

  1. stirringThe 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 16 h
  4. customThe reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL)
  5. customThe excess solvent was removed in vacuo
  6. additionThe mixture was then poured into water (150 mL)
  7. extractionextracted with ethyl acetate (3×100 mL)
  8. dry with materialThe combined organic layers were dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-75a41f5c52d94a8a8dc2d1fd38a1bf74
Source dataset
uspto-grants-2007_05
Patent number
US07223868B2

Reaction notes

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