Ammonium Chloride → 1-[1,3]Dioxolan-2-yl-6,6,6-trifluoro-hexan-3-one

4,4,4-Trifluorobutyric acid chloride (6.4 g from above) in CH2Cl2 (80 ml) was treated with O,N-dimethylhydroxylamine hydrochloride (60.0 mmol, 5.85 g). The mixture was cooled to 0° C., then treated with pyridine (160.0 mmol, 12.9 ml), then allowed to warm to room temperature overnight. The mixture was diluted with CH2Cl2 (200 ml), then washed with brine(2×50 ml). Solvent was removed from the volatile product by simple distillation at atmospheric pressure to provide 20 g of 4,4,4-trifluoro-N-methoxy-N-methyl butyramide, which may be used without further purification. 1H NMR (CDCl3) δ 3.70 (3H, s), 3.19 (3H, s), 2.78-2.65 (2H, m), 2.57-2.40 (2H, m). Mg (92.0 mmol, 2.2 g) in THF (80 ml), under an argon atmosphere, was treated with 2-(2-bromoethyl)-[1,3]dioxolane (80 mmol, 9.4 ml), while keeping the internal temperature below 35° C. with the aid of an ice bath. After the addition was complete, the mixture was stirred for 2 h at room temperature, then cooled to −78° C. Crude 4,4,4-trifluoro-N-methoxy-N-methyl butyramide (20 g, prepared above) in THF (40 ml) was cooled to −78° C., then the freshly prepared Grignard reagent was transferred via cannula into the amide solution at −78° C. The resulting mixture was allowed to warm to room temperature, held at room temperature overnight, then poured into saturated aqueous ammonium chloride (200 ml). The mixture was extracted with ethyl acetate (3×75 ml). The combined organics were washed with brine (2×75 ml) and concentrated under reduced pressure to provide crude 1-[1,3]dioxolan-2-yl-6,6,6-trifluoro-hexan-3-one (18 g) 1H NMR (CDCl3) δ 4.91 (1H, t, J=4.1), 3.97-3.82 (4H, m), 2.70 (2H, t, J=7.3), 2.57 (2H, t, J=7.2), 2.49-2.34 (2H, m), 2.01 (2H, dt, J=7.3, 4.1).

1. custommay be used without further purification
2. customthe internal temperature below 35° C.
3. additionAfter the addition
4. temperaturecooled to −78° C
5. temperatureto warm to room temperature
6. waitheld at room temperature overnight
7. extractionThe mixture was extracted with ethyl acetate (3×75 ml)
8. washThe combined organics were washed with brine (2×75 ml)
9. concentrationconcentrated under reduced pressure

ORD record

ord-a0f5b8f70e794c94b7c9c2f62542e513

Source dataset

uspto-grants-2005_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06872745B2