Uses
Methyl 2-bromonicotinate serves as a precursor in Sonogashira coupling with 1-trans-dichlorobis-ethynyl-4-methoxybenzene to synthesize Methyl 2-((4-methoxyphenyl)ethynyl)nicotinate, and undergoes Suzuki–Miyaura cross-coupling with 2-chlorophenylboronic acid followed by lactonization to produce coumarin-fused pyridine[2][3].
Synthesis
In a 500 mL three-necked flask equipped with a thermometer, 61 mL (0.5 mol) of N,N-diethyl-3-aminoacrylaldehyde, 50 mL of 95% ethanol, and 5.0 g of potassium bicarbonate (KHCO3) were added sequentially, followed by the slow addition of 65 mL (0.6 mol) of methyl cyanoacetate. The assembled reaction apparatus was placed in an ultrasonic apparatus. The ultrasonic radiation conditions were set to 60 °C reaction temperature, 250 W ultrasonic power and 150 KHz frequency to start the reaction. The reaction progress was monitored by thin layer chromatography (TLC) (unfolding agent: petroleum ether to dichloromethane 1:2 v/v, color developer: sublimated iodine) until N,N-diethyl-3-aminoacrolein was fully reacted. Subsequently, hydrogen bromide (HBr) gas was passed into the reaction system, and the reaction was maintained under the above ultrasonic radiation conditions for about 35 minutes and the reaction was tracked to completion by high performance liquid chromatography (HPLC). At the end of the reaction, the pH of the reaction solution was adjusted to 5-6 with 10% potassium hydroxide solution and left to stratify. The aqueous phase was extracted with ethyl acetate (20 mL x 3) and the organic phases were combined. The organic phase was washed with 10 mL of deionized water and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give a light brown liquid methyl 2-bromonicotinate (97.7 g) in 90.5% yield.
References
[1] Patent: CN104945317, 2018, B. Location in patent: Paragraph 0065; 0067; 0068
[2] Curti, F., Tiecco, M., Pirovano, V., Germani, R., Caselli, A., Rossi, E., & Abbiati, G. (2019). p-TSA-Based DESs as "Active Green Solvents" for Microwave Enhanced Cyclization of 2-Alkynyl-(hetero)-arylcarboxylates: an Alternative Access to 6-Substituted 3,4-Fused 2-Pyranones. European Journal of Organic Chemistry, 2019(9), 1904–1914.
https://doi.org/10.1002/ejoc.201801884 [3] Samanta, K., Adak, S., Samanta, S., Patra, S., & Patra, P. (2025). Recent advances in the design and synthesis of coumarins and their derivatives via Suzuki–Miyaura reaction (2002–2024). Monatshefte für Chemie - Chemical Monthly, 156(12), 1239–1281.
https://doi.org/10.1007/s00706-025-03396-4
