Diisopropylamine → Lithium diisopropylamide mono(tetrahydrofuran)

Temperature

-20 °C

LDA/THF was prepared by adding n-BuLi (0.29 mL, 1.6 M/hexanes, 0.46 mmol, 3.0 equiv) to diisopropylamine (65 μL, 0.46 mmol, 3.0 equiv) in 3 mL dry THF under a nitrogen atmosphere in a flame dried schenck flask at −78° C. The resulting solution was warmed to −20° C. and stirred for another 15 min. After the LDA solution was cooled down to −78° C., TMEDA (69 μL, 0.46 mmol, 3.0 equiv) was added slowly via a syringe. Compound S2-1-1 (0.10 g, 0.20 mmol, 1.3 equiv) was dissolved in 1 mL dry THF and added into the LDA solution slowly via a syringe. A dark-red color appeared as soon as addition started. After stirring for 10 min, enone S1-9 (74 mg, 0.15 mmol, 1.0 equiv) in 1 mL dry THF was added slowly a via syringe. After 10 min, LC/MS indicated that the enone was consumed and the product present. The reaction mixture was allowed to slowly warm to −20° C. in 1 h. A phosphate buffer solution (pH 7, 10 mL) was added, followed by the addition of 20 mL saturated aqueous ammonium chloride. The resulting mixture was extracted with dichloromethane (3×15 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting orange-red oil was purified by column chromatography (Biotage 10 g column, 10% to 30% EtOAc in hexanes gradient) to yield the desired compound S2-2-1 (90 mg, 65%).

1. customdried schenck flask at −78° C
2. temperatureAfter the LDA solution was cooled down to −78° C.
3. additionsoon as addition
4. stirringAfter stirring for 10 min
5. waitAfter 10 min
6. customwas consumed
7. temperatureto slowly warm to −20° C. in 1 h
8. additionA phosphate buffer solution (pH 7, 10 mL) was added
9. additionfollowed by the addition of 20 mL saturated aqueous ammonium chloride
10. extractionThe resulting mixture was extracted with dichloromethane (3×15 mL)
11. dry with materialThe combined extracts were dried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customThe resulting orange-red oil was purified by column chromatography (Biotage 10 g column, 10% to 30% EtOAc in hexanes gradient)

ORD record

ord-6859f9420f07416c8fa5b05a154a7677

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09315451B2