Methyl iodide → 2-Methyl-6-(piperidin-1-yl)benzaldehyde

Temperature

-20 °C

To a solution of N,N,N′-trimethylethylenediamine in dry THF (110 mL), cooled to −20° C., n-BuLi (27.3 mL of a 1.6 M solution in hexane, 43.68 mmol, 1.0 eq) was added dropwise. After 15 min, a solution of 2-piperidin-1-ylbenzaldehyde 3b (8.0 g, 42.27 mmol) in THF (20 mL) was added slowly while maintaining the temperature at −20° C. After an additional 15 min, additional n-BuLi (79.25 mL of a 1.6 M solution in hexane, 126.8 mmol, 3.0 eq) was slowly added. The reaction mixture was maintained at −20° C. for 90 h using a cryocool apparatus and then cooled to −78° C. for the addition of methyl iodide (15.8 mL, 253.8 mmol, 6.0 eq). The cooling bath was removed after the addition and the work-up was carried out once the reaction mixture was at RT. The mixture was poured into a cold solution of saturated NH4Cl and extracted 3X with EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated to afford a brown oil which was purified by flash chromatography using a mixture consisting of 5% EtOAc-95% hexane as eluent. The desired 2-methyl-6-piperidin-1-ylbenzaldehyde 3c was isolated as pale yellow oil (3.74 g, 43% yield).

1. waitAfter an additional 15 min
2. temperatureThe reaction mixture was maintained at −20° C. for 90 h
3. customThe cooling bath was removed
4. additionafter the addition
5. customwas at RT
6. additionThe mixture was poured into a cold solution of saturated NH4Cl
7. extractionextracted 3X with EtOAc
8. washThe combined organic layer was washed with brine
9. dry with materialdried over anhydrous MgSO4
10. filtrationfiltered
11. concentrationconcentrated
12. customto afford a brown oil which
13. customwas purified by flash chromatography

ORD record

ord-8ac67a5c6d2f4d1db42913e6279bc402

Source dataset

uspto-grants-2009_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07582766B2