Acetaldehyde → HCID 68771604, compound

Temperature

0 °C

At −78° C. under N2, a solution of diisopropylamine (2.57 ml, 18.2 mmol) in anhydrous THF (13.50 ml) was treated dropwise with a solution of 1.6M n-BuLi in hexane (11.40 ml, 18.2 mmol). The resulting solution was stirred 10 min. at 0° C., cooled to −78° C. and treated dropwise with rel-(4R,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)ethanone (2.3 g, 14.0 mmol, rel-(4R,5R)-/rel-(4S,5R)-98:2) in anhydrous THF (2.2 ml). The resulting solution was stirred 1 h at −78° C., warmed to −20° C., cooled to −78° C. and treated with a solution of acetaldehyde (4.40 ml, 70.1 mmol) in anhydrous THF (13.5 ml). The resulting solution was stirred for 15 min. at −78° C., warmed to −30° C., cooled to −78° C., and treated slowly with a mixture of 2N HCl (11.62 ml) and of a saturated aqueous solution of NaCl (7 ml). The mixture was then warmed to 0° C., the aqueous phase extracted three times with Et2O and the combined organic phases washed with a saturated aqueous solution of NaHCO3, a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaCl, dried (Na2SO4) and concentrated to give 4.06 g of crude product. A solution of the crude product (2.92 g, 14.0 mmol) in toluene (85 ml) was treated with para-toluene sulfonic acid monohydrate (133.5 mg, 0.702 mmol) stirred at 80° C. for 2 h, cooled, poured into a saturated aqueous solution of NaHCO3. The aqueous phase was extracted three times with Et2O and the combined organic phases washed with a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaCl, and concentrated. FC (500 g SiO2, hexane/Et2O 10:0.5) of the crude product (3.4 g) gave two fractions of rel-(4R,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)but-2-en-1-one (Fraction 1: 0.613 g, 23%, 2 steps, rel-(4R,5R)-/rel-(4S,5R)-93:7; Fraction 2: 1.36 g, 51%, 2 steps, rel-(4R,5R)-/rel-(4S,5R)-99.3:0.7).

1. temperaturecooled to −78° C.
2. stirringThe resulting solution was stirred 1 h at −78° C.
3. temperaturewarmed to −20° C.
4. temperaturecooled to −78° C.
5. stirringThe resulting solution was stirred for 15 min. at −78° C.
6. temperaturewarmed to −30° C.
7. temperaturecooled to −78° C.
8. temperatureThe mixture was then warmed to 0° C.
9. extractionthe aqueous phase extracted three times with Et2O
10. washthe combined organic phases washed with a saturated aqueous solution of NaHCO3
11. dry with materiala saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaCl, dried (Na2SO4)
12. concentrationconcentrated
13. customto give 4.06 g of crude product
14. stirringstirred at 80° C. for 2 h
15. temperaturecooled
16. extractionThe aqueous phase was extracted three times with Et2O
17. washthe combined organic phases washed with a saturated aqueous solution of NH4Cl
18. concentrationa saturated aqueous solution of NaCl, and concentrated

ORD record

ord-ea2e04db0ab2490a8e4cfbca62cbfb27

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012391B2