Hydrochloric Acid → [2-ethyl-5-(tetrahydro-2H-thiopyran-4-yl)thiophen-3-yl]methanol

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Reaction Conditions

Reaction Steps

To a solution of ethyl 5-bromo-2-ethylthiophene-3-carboxylate (5.28 g) synthesized in Example 69 (4) in tetrahydrofuran (60 mL) was added dropwise 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (24.1 mL) at −45° C., and the mixture was stirred for 1 hr under an argon atmosphere. A solution of tetrahydro-4H-thiopyran-4-one (7.01 g) in tetrahydrofuran (15 mL) was added dropwise, and the mixture was stirred at −45° C. for 2 hr, and then at room temperature for 1.5 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give a pale-yellow oil. A mixture of the obtained oil, triethylsilane (4.82 mL), methylene chloride (25 mL) and chloroform (50 mL) was cooled to −78° C., trifluoroacetic acid (10 mL) was added, and, under a nitrogen atmosphere, the mixture was stirred −78° C. for 1 hr, and then at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to give colorless oil. The obtained oil in tetrahydrofuran solution (60 was added 1.5M diisobutylaluminum hydride-toluene solution (23.2 mL) at 0° C., and the mixture was stirred for 1 hr. 1.5M Diisobutylaluminum hydride in toluene solution (15.5 mL) was added again, and the mixture was further stirred at 0° C. for 1 hr. 1N Hydrochloric acid was added to quench the reaction, the organic solvent was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (2.76 g, 57%) as a colorless oil.

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