tert-Butoxy bis(dimethylamino)methane → 5-Bromo-2-chloropyridine-4-carbaldehyde

Temperature

120 °C

To a solution of 5-bromo-2-chloro-4-methylpyridine (5.0 g, 20 mmol) in N,N-dimethylformamide (38 mL) was added tert-butoxybis(dimethylamino)methane (7.0 mL, 33.9 mmol). The reaction mixture was heated at 120° C. for 2 hours. The cooled reaction mixture was concentrated in vacuo to afford a thick orange oil, which was redissolved in tetrahydrofuran (40 mL) and slowly poured into a separate flask containing slurry of sodium periodate in water (150 mL) at 0° C. The reaction flask was equipped with an overhead stirrer and allowed to warm to room temperature. The reaction mixture was mixed vigorously for three hours, and then diluted with dichloromethane (150 mL) and filtered. The collected solids were washed with dichloromethane (2 ×150 mL), and the organic layer was separated from the filtrate and washed with saturated sodium bicarbonate solution (50 mL). The aqueous layer was neutralized via addition of solid sodium bicarbonate, and then back-extracted with dichloromethane (100 mL). The organic portions were combined, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 120 g, ISCO, 0-40% ethyl acetate in heptane) to afford the title compound as an off-white solid (4.03 g, 80%). 1H NMR (500 MHz, d6-DMSO) δ 10.10 (s, 1H), 8.85 (s, 1H), 7.81 (s, 1H).

1. customThe cooled reaction mixture
2. concentrationwas concentrated in vacuo
3. customto afford a thick orange oil, which
4. additionslowly poured into a separate flask
5. customThe reaction flask was equipped with an overhead stirrer
6. temperatureto warm to room temperature
7. additionThe reaction mixture was mixed vigorously for three hours
8. filtrationfiltered
9. washThe collected solids were washed with dichloromethane (2 ×150 mL)
10. customthe organic layer was separated from the filtrate
11. washwashed with saturated sodium bicarbonate solution (50 mL)
12. additionThe aqueous layer was neutralized via addition of solid sodium bicarbonate
13. extractionback-extracted with dichloromethane (100 mL)
14. dry with materialdried over sodium sulfate
15. filtrationfiltered
16. customevaporated in vacuo
17. customto afford a residue that
18. customwas purified by flash chromatography (silica, 120 g, ISCO, 0-40% ethyl acetate in heptane)

ORD record

ord-99ecc26071574231a48e14cf2f35cb68

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09206175B2