Tetrahydrofuran → 3-Cyclopentylpropiolonitrile

Temperature

-78 °C

To a oven dried 500 mL 3-neck round bottom flask equipped with a stir bar, a nitrogen inlet, a 125 mL addition funnel and a thermocouple, cyclopentylacetylene (7, 15.0 g, 0.143 mol) and anhydrous tetrahydrofuran (THF, 170 mL, 2.10 mol) were added at room temperature. The resulting solution was then cooled to −78° C. before a solution of 2.5 M n-butyllithium in hexane (63.1 mL, 0.158 mol, 1.1 equiv) was added dropwise over 25 min. The resulting lithium cyclopentylacetylene solution was stirred at −78° C. for 15 minutes before a solution of crude cyanatobenzene (6, 25.0 g, 0.210 mol, 1.5 equiv) in anhydrous tetrahydrofuran (THF, 30.0 mL, 0.400 mol) was added dropwise via a canula at −78° C. The resulting reaction mixture was stirred at −78° C. for an additional 10 min before the cooling batch was removed and the reaction mixture was allowed to gradually warm to room temperature and stirred at room temperature for 1-2 h. When the reaction was deemed complete, the reaction mixture was quenched with a 6 N aqueous sodium hydroxide solution (NaOH, 200 mL) and a 20% aqueous brine solution (200 mL). The aqueous solution was treated with ethyl acetate (EtOAc, 200 mL) before the two layers were separated. The organic layer was dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 0 to 5% ethyl acetate/hexane gradient elution) to afford 3-cyclopentylpropiolonitrile (8, 14.3 g, 17.0 g theoretical, 84% yield for two steps) as a yellow to orange oil. For 8: 1H NMR (DMSO-d6, 400 MHz) δ 2.97 (m, 1H), 1.97 (m, 2H), 1.64 (m, 4H), 1.56 (m, 2H).

1. customTo a oven dried 500 mL 3-neck round bottom flask
2. customequipped with a stir bar, a nitrogen inlet, a 125 mL addition funnel
3. additionwas added dropwise over 25 min
4. additionwas added dropwise via a canula at −78° C
5. customThe resulting reaction mixture
6. customwas removed
7. temperatureto gradually warm to room temperature
8. stirringstirred at room temperature for 1-2 h
9. customthe reaction mixture was quenched with a 6 N aqueous sodium hydroxide solution (NaOH, 200 mL)
10. additionThe aqueous solution was treated with ethyl acetate (EtOAc, 200 mL) before the two layers
11. customwere separated
12. dry with materialThe organic layer was dried over magnesium sulfate (MgSO4)
13. filtrationfiltered
14. concentrationconcentrated under reduced pressure
15. customThe residue was purified by flash column chromatography (SiO2, 0 to 5% ethyl acetate/hexane gradient elution)

ORD record

ord-d353eeedc1af4c398aa4da075eb810b4

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09000161B2