Diisopropylamine → 1-(2-Fluoropyridin-3-yl)ethan-1-one

Temperature

-78 °C

A solution of 3.13 mL (30.90 mmol) of freshly distilled diisopropylamine in 10 mL of anhydrous THF under nitrogen cooled to −78° C. was treated dropwise with 19.31 mL (30.90 mmol) of a 1.6 M solution of n-BuLi in hexanes. The resulting solution was stirred at −78° C. for approximately 20 minutes, and was briefly (5-10 minutes) warmed to −40° C., then recooled to −78° C. At 30 minutes post addition, 3.00 g (30.90 mmol) of 2-fluoropyridine was added dropwise to the reaction. The resulting solution was stirred at −78° C. for 30 minutes. The reaction was treated dropwise with a solution of 3.16 mL (30.90 mmol) of the Weinreb amide (i.e., N-methoxy-n-methylacetamide) in 30 mL of THF. The resulting solution was stirred 18 hours, allowing the bath to slowly evaporate and the reaction temperature to rise to room temperature. The reaction was treated with 5 mL of 1N HCl, and was concentrated to remove most of the THF. The residue was extracted twice with EtOAc, and the combined extracts were washed with 1N HCl, saturated aqueous NaHCO3 solution, and brine, and were dried over anhydrous MgSO4. Filtration and concentration of the filtrate provided a crude orange oil, which was purified by flash chromatography over silica gel with 3:1 hexanes/EtOAc to provide 1.10 g of the title product as an orange oil. 1H NMR (CDCl3): δ 2.72 (s, 3H), 7.33 (m, 1H), 8.34 (m, 1H), 8.41 (m, 1H).

1. custom(5-10 minutes)
2. temperaturewarmed to −40° C.
3. customrecooled to −78° C
4. additionwas added dropwise to the reaction
5. stirringThe resulting solution was stirred at −78° C. for 30 minutes
6. stirringThe resulting solution was stirred 18 hours
7. customto slowly evaporate
8. customto rise to room temperature
9. additionThe reaction was treated with 5 mL of 1N HCl
10. concentrationwas concentrated
11. customto remove most of the THF
12. extractionThe residue was extracted twice with EtOAc
13. washthe combined extracts were washed with 1N HCl, saturated aqueous NaHCO3 solution, and brine
14. dry with materialwere dried over anhydrous MgSO4
15. filtrationFiltration and concentration of the filtrate
16. customprovided a crude orange oil, which
17. customwas purified by flash chromatography over silica gel with 3:1 hexanes/EtOAc

ORD record

ord-0ead606c06ba4f6485de9cc7efd9b1dc

Source dataset

uspto-grants-2010_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07781454B2