Uses
4-Methoxypyridine-3-carboxaldehyde, is an intermediate for the synthesis of 4-Hydroxy-3-pyridinecarboxylic Acid (H952780). It can also be used for the preparation of 7,8-dimethylquinolines derivatives as potential antimicrobial and antifungal agents.
Synthesis
Example 2 Preparation of 4-methoxypyridine-3-carbaldehyde
To a stirred solution of tetrahydrofuran (380 mL) was added tert-butyllithium (90.6 mL, 154 mmol; 1.7 M in pentane) via cannula under nitrogen protection. The reaction mixture was cooled to -78°C, followed by dropwise addition of 2-bromotoluene (11.3 mL, 74.1 mmol). The reaction mixture was stirred at -78°C for 1 hour. Then, 4-methoxypyridine (5.79 mL, 57 mmol) was added dropwise to the reaction mixture at -78°C and the resulting mixture was stirred at -23°C for 3 hours. The reaction mixture was again cooled to -78°C, N,N-dimethylformamide (6.62 mL, 85.5 mmol) was added and stirring was continued at -78°C for 1 hour. The reaction mixture was slowly quenched with saturated aqueous sodium chloride solution (100 mL) at -78°C, followed by slow warming to room temperature. Ether (200 mL) was added to the reaction mixture and the organic and aqueous layers were separated. The aqueous layer was extracted with ether (2 x 150 mL) and the combined organic layers were dried with anhydrous potassium carbonate (20 g). The potassium carbonate was removed by filtration, the filter cake was washed with ether (100 mL), and the solvent was removed by concentration under reduced pressure. The resulting crude product, 4-methoxy-3-pyridinecarboxaldehyde, was purified by silica gel column chromatography (eluent ratio 5:95 ethanol:ethyl acetate) to afford 4.79 g of the target product as a yellow solid (61% yield; purity >98% as determined by 1H NMR).
References
[1] Tetrahedron Letters, 2006, vol. 47, # 1, p. 39 - 41
[2] Tetrahedron Letters, 2000, vol. 41, # 24, p. 4777 - 4780
[3] Patent: WO2005/42514, 2005, A2. Location in patent: Page/Page column 25
[4] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 419 - 434
[5] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
