| 62% |
Stage #1: methyl methylsulfinylmethyl sulfide With n-butyllithium In tetrahydrofuran; hexane at -20℃; for 0.5h; Inert atmosphere;
Stage #2: 2,2,2-trifluoro-1-(3-methoxyphenyl)ethanone In tetrahydrofuran; hexane at -20℃; for 4h; Inert atmosphere; Further stages; |
Preparation of 6-iodo-2-methylthio-3-trifluoromethyl-5-triflyloxybenzo[b]thiophene (24)S7
To a solution of formaldehyde dimethyl dithioacetal S-oxide (0.20 mL, 2.0 mmol) dissolved in THF(2.0 mL) was added n-butyllithium (2.6 M, hexane solution, 0.77 mL, 2.0 mmol, 1.0 equiv) at -20 °C.After stirring for 30 min at the same temperature, to the mixture was added 3’-methoxy-2,2,2-trifluoroacetophenone (490 mg, 2.40 mmol, 1.2 equiv) at -20 °C and the mixture was stirred for4 h at the same temperature. To the mixture was added acetic anhydride (0.20 mL, 2.2 mmol, 1.1equiv) at -20 °C and, after stirring for 12 h at the same temperature, to the mixture was addedsaturated aqueous NH4Cl (20 mL) at the same temperature. The mixture was extracted with EtOAc (10mL × 3), and the combined organic extract was washed with brine (10 mL), dried (Na2SO4), and after filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in benzene(2.0 mL) and tert-butyl alcohol (2.0 mL) and to this solution was added potassium tert-butoxide (269mg, 2.40 mmol, 1.2 equiv) at room temperature. After stirring for 1 h at the same temperature, to themixture was added saturated aqueous NH4Cl (4 mL). The mixture was extracted with EtOAc (10 mL ×3), and the combined organic extract was washed with brine (10 mL), dried (Na2SO4), and afterfiltration, the filtrate was concentrated under reduced pressure. Purification by flash columnchromatography (silica-gel 30 g, n-hexane/EtOAc = 5/1) provided a stereoisomeric mixture of methyl3,3,3-trifluoro-2-(3-methoxyphenyl)-1-methylsulfinyl-1-propenyl sulfide (E/Z = 1/1, 386 mg, 1.25mmol, 62%).To a stereoisomeric mixture of methyl 3,3,3-trifluoro-2-(3-methoxyphenyl)-1-methylsulfinyl-1-propenyl sulfide (E/Z = 1/1, 890 mg, 2.86 mmol) dissolved in toluene (40 mL) were added K2CO3(1.19 g, 8.61 mmol, 3.0 equiv) and trifluoromethanesulfonic anhydride (0.620 mL, 3.72 mmol, 1.3equiv) at room temperature. After stirring for 1 h at the same temperature, to the mixture was added2-aminoethanol (0.858 mL, 14.3 mmol, 5.0 equiv) was added at room temperature. After stirring for 3h at the same temperature, to the mixture was added saturated aqueous NaHCO3 (40 mL). The mixturewas extracted with EtOAc (20 mL × 3), and the combined organic extract was washed with brine (20mL), dried (Na2SO4), and after filtration, the filtrate was concentrated under reduced pressure. Theresidue was purified by flash column chromatography (silica-gel 40 g, n-hexane/CH2Cl2 = 10/1; then,silica-gel 60 g, n-hexane/CH2Cl2 = 15/1) to give 5-methoxy-2-methylthio-3-trifluoromethylbenzo[b]-thiophene (323 mg, 1.16 mmol, 40.7%).To a solution of 5-methoxy-2-methylthio-3-trifluoromethylbenzo[b]thiophene (278 mg, 1.00 mmol)dissolved in CH2Cl2 (2.0 mL) was added boron tribromide (1.0 M, dichloromethane solution, 2.00 mL,2.0 mmol, 2.0 equiv) at -78 °C. After warming to -20 °C, the mixture was stirred for 24 h, and to thiswere added MeOH (2 mL) and water (10 mL). The mixture was extracted with EtOAc (10 mL × 3),and the combined organic extract was washed with brine (10 mL), dried (Na2SO4), and after filtration,the filtrate was concentrated under reduced pressure. The residue was purified by flash columnchromatography (silica-gel 30 g, n-hexane/CH2Cl2 = 1/2 to 1/3) to give 5-hydroxy-2-methylthio-3-trifluoromethylbenzo[b]thiophene (221 mg, 0.837 mmol, 83.8%).To a solution of 5-hydroxy-2-methylthio-3-trifluoromethylbenzo[b]thiophene (780 mg, 2.95 mmol)dissolved in CH2Cl2 (4.5 mL) and MeOH (4.5 mL) were added N-iodosuccinimide (NIS) (663 mg,2.95 mmol, 1.0 equiv) and concentrated sulfuric acid (1 drop, ca. 10 mg) at room temperature. Afterstirring for 2 h at the same temperature, to the mixture was added saturated aqueous sodium thiosulfate(10 mL). The mixture was extracted with EtOAc (20 mL × 3), and the combined organic extract waswashed with brine (20 mL), dried (Na2SO4), and after filtration, the filtrate was concentrated underreduced pressure. The residue was dissolved in acetonitrile (60 mL) and to this solution were added1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (673 mg, 4.43 mmol, 1.5 equiv) and N-phenyl-bis-(trifluoromethanesulfonimide) (PhNTf2) (1.58 g, 4.43 mmol, 1.5 equiv) at 0 °C. After stirring for 5 min at the same temperature, to the mixture was added water (20 mL). The mixture was extracted withEtOAc (20 mL × 3), and the combined organic extract was washed with brine (20 mL), dried (Na2SO4),and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified byflash column chromatography (silica-gel 30 g, n-hexane/EtOAc = 20/1) to give 6-iodo-2-methylthio-3-trifluoromethyl-5-triflyloxybenzo[b]thiophene (24) (1.09 g, 2.09 mmol, 70.8%). |
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