反应详情

温度

-78 °C

3,4-Dimethyl-thiophene-2,5-dicarboxylic acid monoethyl ester is prepared according to a literature procedure (H. Wynberg et al., J. Org. Chem. 29 (1964) 1919-1921); LC-MS: tR=0.70 min, [M+H]+=not detectable; 1H NMR (D6-DMSO): δ 1.26-1.33 (m, 3H), 2.42 (s, 6H), 4.22-4.33 (m, 2H), 12.91 (s br, 1H). b) To a solution of 3,4-dimethyl-thiophene-2,5-dicarboxylic acid monoethyl ester (6.70 g, 29.4 mmol) in THF (70 mL), a solution of diisobutylaluminium hydride (DIBAL, 90 mL, 1 M in THF) is added at −78° C. The mixture is stirred at −78° C. for 30 min, then at −10° C. for 1 h before another portion of DIBAL (30 mL) is added. Stirring is continued at −10° C. for 30 min. Four more portions of DIBAL (30 mL) are added each time after stirring of the mixture for 30 min at −10° C. The reaction mixture is carefully quenched with water, diluted with 2 N aq. NaOH solution and extracted with DCM. The organic extracts are disgarded. The aq. phase is acidified by adding 25% aq. HCl and then extracted twice with EA. The organic extracts are washed with brine, dried over MgSO4, filtered, concentrated and dried under high vacuum to give crude 5-hydroxymethyl-3,4-dimethyl-thiophene-2-carboxylic acid (3.00 g) as a brownish solid; LC-MS: tR=0.66 min, [M+H]+=not detectable. c) A mixture of 5-hydroxymethyl-3,4-dimethyl-thiophene-2-carboxylic acid (3.00 g, 8.06 mmol) and MnO2 (2.55 g, 29.3 mmol) in acetic acid (60 mL) is stirred at 80° C. for 3 h, then at 70° C. for 16 h. The mixture is filtered over Hyflo and the filtrate is concentrated. The crude product is purified by CC on silica gel eluting with DCM containing 10% of methanol. The obtained brownish solid is further purified by suspending the material in acetonitrile and methanol. The solid material is removed by filtration and the filtrate is further purified by prep. HPLC (XBridge Prep C18, 30×75 mm, 5 μm, acetonitrile/water (0.5% HCOOH), 10% to 95% acetonitrile) to give the title compound (435 mg) as a yellow solid; 1H NMR (D6-DMSO): δ 2.43 (s br, 6H), 10.16 (s, 1H), 12.35 (s br, 1H).

1. stirringStirring
2. waitis continued at −10° C. for 30 min
3. stirringafter stirring of the mixture for 30 min at −10° C
4. customThe reaction mixture is carefully quenched with water
5. additiondiluted with 2 N aq. NaOH solution
6. extractionextracted with DCM
7. additionby adding 25% aq. HCl
8. extractionextracted twice with EA
9. washThe organic extracts are washed with brine
10. dry with materialdried over MgSO4
11. filtrationfiltered
12. concentrationconcentrated
13. customdried under high vacuum