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

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Reaction Steps

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.

Provenance & Evidence