Isobutyric Acid → 2,2-Dimethyl-3-(thiophen-2-yl)propanoic acid

HRID 462672Notes

Reaction equation

HRID 462672 reaction equation
[H-].[Na+].C(NC(C)C)(C)C.[C:10]([OH:15])(=[O:14])[CH:11]([CH3:13])[CH3:12].C([Li])CCC.CCCCCC.Cl[CH2:28][C:29]1[S:30][CH:31]=[CH:32][CH:33]=1>O.O1CCCC1>[CH3:12][C:11]([CH3:13])([CH2:28][C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[C:10]([OH:15])=[O:14]

Participants

9

Reactant 6

HCID 6590Isobutyric AcidHCID 7912DiisopropylamineHCID 8058HexaneHCID 24758Sodium hydrideHCID 698302-(Chloromethyl)thiopheneHCID 178418339Butyllithium

Product 1

HCID 104877462,2-Dimethyl-3-(thiophen-2-yl)propanoic acidYield 91%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 57% oil emulsion of sodium hydride (3.1 g, 0.07 mole), tetrahydrofuran (68 mL) and diisopropylamine (6.87 g, 0.07 mole) was stirred under nitrogen atmosphere as isobutyric acid (5.98 g, 0.07 mole) was added dropwise. The mixture was heated at reflux for 15 min to complete formation of the salt. After cooling to 0°, a solution of n-butyllithium in hexane (42 mL of 1.6 molar solution, 0.07 mole) was added in small portions while holding the temperature below 10°. The resulting turbid solution was kept at 0° for 15 min and then warmed to 30°-35° for 30 min. After again cooling to 0°, 2-chloromethylthiophene (9 g, 0.07 mole) was added dropwise over 15-20 min while holding the temperature between 0° and 50°. The mixture was kept at 0° for 30 min, in the range of 30°-35° for 1 hr and was then cooled to 15°. Water (90 mL) was added dropwise and the aqueous layer was separated. The organic phase was washed with a mixture of water (50 mL) and ether (75 mL). The aqueous extracts were combined, washed with ether and then acidified with conc HCl. The oily product was extracted with ether and the combined ether extracts dried (MgSO4). Removal of the ether in vacuo gave 11.4 g (91%) of 2,2-dimethyl-3-(2-thienyl)propanoic acid of sufficient purity for use.

Workup

  1. additionwas added dropwise
  2. temperatureThe mixture was heated
  3. temperatureat reflux for 15 min
  4. temperatureAfter cooling to 0°
  5. customthe temperature below 10°
  6. temperaturewarmed to 30°-35° for 30 min
  7. temperatureAfter again cooling to 0°
  8. customthe temperature between 0° and 50°
  9. waitThe mixture was kept at 0° for 30 min, in the range of 30°-35° for 1 hr
  10. temperaturewas then cooled to 15°
  11. customthe aqueous layer was separated
  12. washThe organic phase was washed with a mixture of water (50 mL) and ether (75 mL)
  13. washwashed with ether
  14. extractionThe oily product was extracted with ether
  15. dry with materialthe combined ether extracts dried (MgSO4)
  16. customRemoval of the ether in vacuo

Sources & evidence

ORD record
ord-554cc8d47a374865a463af05f883e9dc
Source dataset
uspto-grants-1985_05
Patent number
US04517188

Reaction notes

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