Synthesis
General procedure for the synthesis of 5-methylpyridine-2-aldehyde from 2-bromo-5-methylpyridine and N,N-dimethylformamide: 50 g (290 mmol) of 2-bromo-5-methylpyridine was dissolved in 2500 mL of diethyl ether and cooled to -78 °C. Subsequently, 150 mL (380 mmol) of n-butyllithium (nBuLi) was slowly added dropwise and the reaction mixture was stirred at -78 °C for 2 hours. Next, 31.5 mL (407 mmol) of N,N-dimethylformamide (DMF) was slowly added and the reaction mixture was allowed to gradually warm up to room temperature. Upon completion of the reaction, water was added to the mixture for quenching. The organic and aqueous layers were separated and the aqueous layer was extracted three times with ethyl acetate. All organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to give a brown oil. The residue was purified by fast column chromatography (eluent: heptane/ethyl acetate, gradient 0 to 25% ethyl acetate) to give 19 g (39% yield) of brown solid product. Mass spectrum (APCI): m/z 122 ([M+H]+). 1H NMR (CDCl3, 360 MHz) δ (ppm): 2.48 (s, 3H, CH3); 7.70 (dd, J = 7.9, 2.0 Hz, 1H, pyridine H4); 7.91 (d, J = 7.7 Hz, 1H, pyridine H3); 8.68 (s, 1H, pyridine H6); 10.10 (s, 1H, aldehyde group).
References
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 8, p. 2238 - 2243
[2] Angew. Chem., 2018, vol. 130, # 8, p. 2260 - 2265,6
[3] Patent: WO2009/60030, 2009, A1. Location in patent: Page/Page column 38-39
[4] Chemistry - A European Journal, 2008, vol. 14, # 17, p. 5313 - 5328
[5] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 24, p. 6763 - 6770
