Methyl iodide → 2,4-Dimethylthiophene-3-carboxylic acid

Temperature

-78 °C

n-Butyllithium (2.5 M in hexanes, 18.6 mL, 46 mmol) was added to a pre-cooled solution of 4-methylthiophene-3-carboxylic acid (3.0 g, 21 mmol) in dry tetrahydrofuran (THF, 35 mL) at −62° C. The reaction mixture was stirred at −78° C. for an hour, allowed to warm to −40° C. and re-cooled to −78° C. before adding iodomethane (3.28 mL, 7.49 g, 53 mmol). After addition, the reactants were stirred at −78° C. for an hour and then allowed to warm to room temperature over 14 hours and quenched with water (20 mL). The organic phase was extracted with dilute sodium hydroxide (0.2 N, 3×30 mL). The combined aqueous extracts were washed with ether (2×30 mL), cooled in an ice bath and acidified to pH 3 using concentrated hydrochloric acid. The resultant precipitate was extracted with ether (3×50 mL). The combined ethereal extracts were washed with water (50 mL) and brine (50 mL), dried over magnesium sulphate, concentrated under reduced pressure and recrystallised from ethyl acetate/hexane to give product as an amorphous white solid (2.7 g, 82%): mp 164-165° C.; 1H NMR (CDCl3) δ 6.65 (q, 1H), 2.73 (s, 3H), 2.43 (d, 3H); EI/MS 156 m/e (M+); IR (liq film) 1664 cm−1; Calcd for C7H8O2S: C, 53.8; H, 5.16; Found: C, 53.8; H, 5.11.

1. temperatureto warm to −40° C.
2. temperaturere-cooled to −78° C.
3. additionAfter addition
4. stirringthe reactants were stirred at −78° C. for an hour
5. temperatureto warm to room temperature over 14 hours
6. customquenched with water (20 mL)
7. extractionThe organic phase was extracted with dilute sodium hydroxide (0.2 N, 3×30 mL)
8. washThe combined aqueous extracts were washed with ether (2×30 mL)
9. temperaturecooled in an ice bath
10. extractionThe resultant precipitate was extracted with ether (3×50 mL)
11. washThe combined ethereal extracts were washed with water (50 mL) and brine (50 mL)
12. dry with materialdried over magnesium sulphate
13. concentrationconcentrated under reduced pressure
14. customrecrystallised from ethyl acetate/hexane

ORD record

ord-8f378334d3e74474bbfc3117f6a4c0be

Source dataset

uspto-grants-2005_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06949576B2