Acetaldehyde → 3-Butyn-2-ol, 1-(4-fluorophenoxy)-, (2S)-

A solution of R-Alpine-Borane® (0.5 M in THF, 930 mL, 465 mmol) was evaporated to dryness under vacuum to get about 150 g of a thick syrup. 4-(4-Fluorophenoxy)-1-butyn-3-one (27.6 g, 155 mmol) was added and when an exothermic reaction was observed, the reaction mixture was cooled with an ice/water bath, then allowed to warm to ambient temperature. After two days, the reaction mixture was cooled to 0° C. and acetaldehyde (26 mL, 465 mmol) was added to quench the excess reagent. After stirring at ambient temperature for 2 hours the reaction mixture was placed under vacuum and stirred first at 0° C. for one hours, then at 65° C. for 2 hours. The reaction mixture was cooled to ambient temperature and ether (300 mL) was added under nitrogen. Ethanolamine (30 mL, 465 mmol) was added drop-wise at 0° C. and the resulting reaction mixture was stored in the freezer overnight. The resulting precipitate was removed by filtration and washed with cold ether. The combined filtrates were concentrated under vacuum. The crude product was purified by flash chromatography on a 2.5 L column of silica gel with 10–25% ethyl acetate in hexane as eluant to obtain 27 g of (3S)-4-(4-fluorophenoxy)-3-hydroxy-1-butyne, a compound of formula (BB), in quantitative yield; 1H NMR (CDCl3) δ 2.56 (s, 1H), 4.10 (m, 2H), 4.78 (m, 1H), 6.85 (m, 2H), 7.0 (m, 2H). This material was determined to be about 64% ee based on chiral HPLC of its 3,5-dinitrobenzoyl ester (see below).

1. customwhen an exothermic reaction
2. temperaturethe reaction mixture was cooled with an ice/water bath
3. temperaturethe reaction mixture was cooled to 0° C.
4. customto quench the excess reagent
5. stirringstirred first at 0° C. for one hours
6. waitat 65° C. for 2 hours
7. temperatureThe reaction mixture was cooled to ambient temperature
8. additionether (300 mL) was added under nitrogen
9. customthe resulting reaction mixture
10. customwas stored in the freezer overnight
11. customThe resulting precipitate was removed by filtration
12. washwashed with cold ether
13. concentrationThe combined filtrates were concentrated under vacuum
14. customThe crude product was purified by flash chromatography on a 2.5 L column of silica gel with 10–25% ethyl acetate in hexane as eluant

ORD record

ord-2f1842298e0b4bc9a48ae079d313d6a9

Source dataset

uspto-grants-2007_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07223798B2