Diisopropylamine → 2-Chloro-3-pyridinecarboxaldehyde

Temperature

-78 °C

THF (200 mL) in a dry flask under N2 is chilled by placing the flask in a dry-ice/acetone bath at −78° C. Butyllithium (125 mL, 200 mmol) is added drop-wise, followed by the drop-wise addition of iodobenzene (11.19 mL, 100 mmol) in THF (10 mL). The solution is allowed to stir for 30 min at −78° C. Diisopropylamine (0.70 mL, 5 mmol) in THF (3 mL) and 2-chloropyridine (9.46 mL, 100 mmol) in THF (30 mL) are added successively in a drop-wise manner, and the solution is stirred for 1 h at −40° C. Formyl piperidine (11.1 mL, 100 mmol) in THF (25 mL) is added drop-wise, and the solution is stirred for 1 h at −40° C. The reaction is quenched with 40 mL 6N HCl, diluted with 250 mL ether, and a small amount of sodium thiosulfate solution is added to remove the iodine color. The solution is neutralized with saturated NaHCO3, filtered, and extracted with ether (3×150 mL). The combined organic layer is dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is chromatographed over 600 g slurry-packed silica, eluting with 20% EtOAc/hexane. The fractions with the desired compound are collected and concentrated to afford 2-chloronicotinaldehyde (C90) as a pale orange solid (54% yield). MS (EI) for C6H4ClNO, m/z: 141 (M)+.

1. customat −78° C
2. stirringthe solution is stirred for 1 h at −40° C
3. stirringthe solution is stirred for 1 h at −40° C
4. customThe reaction is quenched with 40 mL 6N HCl
5. additiondiluted with 250 mL ether
6. additiona small amount of sodium thiosulfate solution is added
7. customto remove the iodine color
8. filtrationfiltered
9. extractionextracted with ether (3×150 mL)
10. dry with materialThe combined organic layer is dried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customThe crude material is chromatographed over 600 g slurry-packed silica
14. washeluting with 20% EtOAc/hexane
15. customThe fractions with the desired compound are collected
16. concentrationconcentrated

ORD record

ord-2f1cf984a2054b7fa5f6fbef4229aab7

Source dataset

uspto-grants-2006_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07067515B2