Uses
2,3-Dibromo-5-methylpyridine serves as a substrate for the synthesis of heterocyclic phenothiazines and regioselective cross-coupling products[2][3]. It functions as an additive in iododesilylation reactions, where it provides a slight yield improvement compared to other pyridine-based additives[1].
Synthesis
2-Amino-3-bromo-5-methylpyridine (187 mg, 1.00 mmol) was added to a 30 mL three-necked flask, followed by the addition of 48% aqueous hydrogen bromide (1 mL) to dissolve the feedstock. The reaction mixture was cooled in an ice bath, keeping the internal temperature in the range of 2 to 5 °C, and bromine (154 μL, 3.00 mmol) was slowly added dropwise. After the dropwise addition, stirring was continued at the same temperature for 10 min. Subsequently, a solution of sodium nitrite (174 mg, 2.5 mmol) dissolved in water (500 μL) was added dropwise to the reaction system while keeping the temperature unchanged, and stirring was continued for 1 h after completion of the dropwise addition. After completion of the reaction, a solution of sodium hydroxide (377 mg, 9.4 mmol) dissolved in water (2 mL) was added slowly and the mixture was stirred for 1 h at room temperature. The reaction solution was transferred to a partition funnel and separated by extraction with ethyl acetate (10 mL) and water (10 mL), and the aqueous phase was extracted once more with ethyl acetate (10 mL). The organic phases were combined and washed sequentially with 5% aqueous sodium sulfite (5 mL) and saturated saline (10 mL), then dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to afford the target product 2,3-dibromo-5-methylpyridine (244 mg, 0.97 mmol) as a yellow solid in 97% yield. The product was analyzed by 1H-NMR (CDCl3, TMS, 300 MHz) δ (ppm): 2.30 (s, 3H), 7.73 (d, 1H, J = 1.5 Hz), 8.14 (d, 1H, J = 1.2 Hz); 13C-NMR (CDCl3, TMS, 300 MHz) δ (ppm): 17.41, 123.16. 134.13, 140.39, 142.29, 148.57; high-resolution mass spectrometry (C6H5Br2N) Theoretical: [M+] 248.8789, Measured: [M+] 248.8786; Melting point 54.2 °C.
References
[1]Bloux, H., Dahiya, A., Hébert, A., Fabis, F., Schoenebeck, F., & Cailly, T. (2023). Base‐Mediated Radio‐Iodination of Arenes by Using Organosilane and Organogermane as Radiolabelling Precursors. Chemistry – A European Journal, 29(19).
https://doi.org/10.1002/chem.202203366 [2]Hu, W., & Zhang, S. (2015). Method for the Synthesis of Phenothiazines via a Domino Iron-Catalyzed C–S/C–N Cross-Coupling Reaction. The Journal of Organic Chemistry, 80(12), 6128–6132.
https://doi.org/10.1021/acs.joc.5b00568 [3]Hikawa, H., & Yokoyama, Y. (2010). Cross-coupling reaction on N-(3,5-dibromo-2-pyridyl)piperazines: regioselective synthesis of 3,5-disubstituted pyridylpiperazines. <i>Tetrahedron</i>, <i>66 49</i>, Pages 9552-9559.
https://doi.org/10.1016/j.tet.2010.09.100
