Reaction #162532

Reaction equation

EtOAc

lithium diisopropylamide

2-Chloro-8-fluoroquinoline

acetaldehyde

→

1-(2-chloro-8-fluoroquinolin-3-yl)ethanol

Yield 50.0%

Solvents

THF

Conditions

Workup

1. 1
   workup.ADDITIONTo this solution was added freshly
2. 2
   Otherprepared
3. 3
   Otherover 5 min
4. 4
   workup.WAITAfter 30 min at −78° C.
5. 5
   Otherthe reaction was quenched with 50% saturated NH4Cl solution
6. 6
   workup.ADDITIONdiluted with EtOAc
7. 7
   OtherThe layers were separated
8. 8
   Washwashed with brine
9. 9
   Dryingdried over MgSO4
10. 10
    Filtrationfiltered
11. 11
    OtherThe crude reaction mixture
12. 12
    Washeluted with 8:2 hexanes
13. 13
    workup.ADDITIONFractions containing product
14. 14
    Washa closely (second) eluting regioisomer
15. 15
    Otherwere collected
16. 16
    ConcentrationThe fractions were concentrated
17. 17
    TemperatureEtOAc at reflux for 30 min
18. 18
    TemperatureAfter cooling to rt
19. 19
    Filtrationthe solid was filtered
20. 20
    Washwashed with a small amount of cold 9:1 hexanes

Procedure

2-Chloro-8-fluoroquinoline (5.00 g, 27.5 mmol) was dissolved in THF (60 mL) and cooled to −78° C. To this solution was added freshly prepared and titrated lithium diisopropylamide (1M solution in THF, 30 mL, 30 mmol, 1.1 eq) over 5 min. The reaction was allowed to stir at −78° C. for 20 min, after which time acetaldehyde (2.3 mL, 41.3 mmol, 1.5 eq.) was added via syringe over 30 seconds (exothermic). After 30 min at −78° C., the reaction was quenched with 50% saturated NH4Cl solution and diluted with EtOAc. The layers were separated and washed with brine, dried over MgSO4, and filtered. The crude reaction mixture was deposited on 30 g of silica gel and passed through a plug of 60 g of silica gel, eluted with 8:2 hexanes:EtOAc. Fractions containing product and a closely (second) eluting regioisomer were collected. The fractions were concentrated and the crude solid was slurried in 140 mL of 9:1 hexanes:EtOAc at reflux for 30 min. After cooling to rt, the solid was filtered and washed with a small amount of cold 9:1 hexanes:EtOAc to afford pure 1-(2-chloro-8-fluoroquinolin-3-yl)ethanol (3.1 g, 13.7 mmol, 50% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (br s, 1H), 7.64 (td, J=7.8, 5.1 Hz, 1H), 7.41 (ddd, J=10.2, 7.4, 1.2 Hz, 1H), 5.39 (qdd, J=6.3, 3.9, 0.8 Hz, 1H), 2.22 (d, J=3.9 Hz, 1H), 1.62 (d, J=6.3 Hz, 3H).

Source