Cyclohexane → 1-(5-Chloropyridin-2-yl)ethan-1-one

Temperatur

-74 °C

A two liter 4 neck flask was equipped with a stirrer, a thermometer and a 250 mL addition funnel. The reaction setup was flushed with nitrogen overnight. A 1.3 M cyclohexane solution of sec-butyllithium (222 mL, 0.289 mol) was charged to the addition funnel with a cannula. 2-Bromo-5-chloropyridine (57.72 g, MW=192.4, 0.30 mol) and 600 mL of ethyl ether were charged to the flask and then cooled in an acetone/dry ice bath. The temperature of the resultant slurry was -76° C. The sec-butyllithium was added dropwise at a rate to maintain the temperature at -74° C. or lower. The addition took 1.5 hours. When the addition was complete the addition funnel was rinsed with 20 mL of ethyl ether, then charged with 30.7 mL of N,N-dimethylacetamide (MW=87.12, d=0.937, 0.330 mol) and 30 mL of ethyl ether. Ten minutes after the completion of the sec-butyllithium addition, the N,N-dimethylacetamide solution was added dropwise to the reaction mixture, again maintaining the temperature at -74° C. or less. This addition took about 40 minutes. The reaction mixture was held at -76° C. for one hour after the N,N-dimethylacetamide addition was complete, then the bath was removed and the temperature allowed to warm to -30° C. At this temperature the cold bath was replaced and the reaction was quenched with 200 mL of 3 N HCl. The reaction mixture was allowed to warm to room temperature and held overnight. The phases were separated, the ethyl ether phase washed with water and saturated brine and then dried over anhydrous MgSO4. The ethyl ether was stripped, the crude product dissolved in methylene chloride and then treated with one weight equivalent of silica gel. The resulting slurry was filtered through Celite and stripped. The product was recrystallized from hexane to give 29.35 g of 2-acetyl-5-chloropyridine (65% yield based on sec-butyllithium, the limiting reagent).

1. additiona thermometer and a 250 mL addition funnel
2. customThe reaction setup was flushed with nitrogen overnight
3. temperaturecooled in an acetone/dry ice bath
4. customwas -76° C
5. additionThe addition
6. additionWhen the addition
7. washwas rinsed with 20 mL of ethyl ether
8. temperatureagain maintaining the temperature at -74° C. or less
9. additionThis addition
10. waittook about 40 minutes
11. waitThe reaction mixture was held at -76° C. for one hour
12. customthe bath was removed
13. temperatureto warm to -30° C
14. customthe reaction was quenched with 200 mL of 3 N HCl
15. temperatureto warm to room temperature
16. waitheld overnight
17. customThe phases were separated
18. washthe ethyl ether phase washed with water and saturated brine
19. dry with materialdried over anhydrous MgSO4
20. dissolutionthe crude product dissolved in methylene chloride
21. additiontreated with one weight equivalent of silica gel
22. filtrationThe resulting slurry was filtered through Celite
23. customThe product was recrystallized from hexane

ORD-Eintrag

ord-d203d82527c4440eb2230ae427d9a51d

Quelldatensatz

uspto-grants-2000_04

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US06054583