Synthesis
The general procedure for the synthesis of 2-bromo-3-methyl-5-formylpyridine from N-formylmorpholine and 2,5-dibromo-3-methylpyridine is as follows:
Method 4: Preparation of 6-bromo-5-methylnicotinaldehyde
1. A solution of 2,5-dibromo-3-methylpyridine (5.1 g, 20.30 mmol) in tetrahydrofuran (25 ml) was slowly added dropwise to a solution of 2M isopropylmagnesium chloride (10.7 ml, 21.3 mmol) in tetrahydrofuran which had been pre-cooled to 0 °C at 0 °C.
2. The reaction mixture was stirred at 0°C for 2 hours, followed by continued stirring at room temperature for 1 hour.
3. a solution of tetrahydrofuran (25 ml) of 4-formylmorpholine (2.1 ml, 20.3 mmol) was slowly added dropwise to the reaction mixture, and after completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour.
4. The reaction mixture was poured into water and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure.
5. The residue was purified by fast column chromatography to afford the target product 2-bromo-3-methyl-5-formylpyridine (3.0 g, 74% yield) using isohexane solution of 10% ethyl acetate as eluent.
NMR spectrum (DMSO-d6): δ 2.44 (s, 3H), 8.19 (s, 1H), 8.73 (s, 1H), 10.09 (s, 1H).
References
[1] Patent: US2008/119451, 2008, A1. Location in patent: Page/Page column 35
[2] Patent: WO2007/71956, 2007, A1. Location in patent: Page/Page column description
[3] Patent: US2012/184520, 2012, A1. Location in patent: Page/Page column 24
