34160-40-2

Light yellow Flakes

6-Bromopyridine-2-carbaldehyde can be a useful synthetic intermediate.

6-Bromopyridine-2-carboxaldehyde is used in the study of a rhodium-catalyzed, reductive aldol coupling with divinyl ketones leading to syn ?-hydroxyenones. It is also used as a building block for Tris[(pyridyl)methyl]amine ligands.

To a 12 L three-necked flask equipped with a mechanical stirrer, addition funnel, nitrogen inlet and thermocouple sleeve was added n-butyllithium (BuLi, 619 mL, 1.55 mol). Anhydrous toluene (750 mL) was then added and the reaction system was cooled to -15 °C in an ice/methanol bath. Butylmagnesium chloride (BuMgCl, 387 mL, 0.774 mol) was added slowly over a period of 30 to 45 minutes, with the rate of addition being controlled so that the reaction temperature did not exceed 0°C. A fine white to gray suspension was formed during the reaction. The suspension was continued to be stirred at -15 °C for 30 min. During this time, 2,6-dibromopyridine (500 g, 2.11 mol) was dissolved in anhydrous toluene (3 L), which was slightly heated if necessary to promote dissolution. After stirring is complete, the 2,6-dibromopyridine solution is transferred to a dosing funnel and slowly added dropwise to the reaction flask at a rate not exceeding -5 °C (about 1.5 h). After the dropwise addition was completed, stirring of the reaction mixture was continued for 45 minutes. A small amount of the reaction solution was quenched in 20% aqueous citric acid and the extent of metal exchange was analyzed by 1H NMR and TLC (25% ethyl acetate/heptane). Toluene (750 mL) and N,N-dimethylformamide (DMF, 250 mL) were added to another 12 L three-necked flask equipped with a mechanical stirrer, nitrogen inlet, and thermocouple cannula and cooled to -15 °C in an ice/methanol bath. The initial reaction solution was transferred to the toluene/DMF mixture through a cannula at a rate not exceeding 5°C. After the transfer was complete, the reaction mixture was stirred for 45 minutes and the completion of the reaction was confirmed by TLC. The reaction solution was transferred to a partition funnel containing 4 L of water and citric acid (1 kg), stirred for 15 min and left to stratify. The organic layer was washed sequentially with 4 L of water and 4 L of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to afford the intermediate 6-bromopyridine-2-carbaldehyde as an off-white to yellow solid (355.7 g, 90% yield).

[1] Journal of Organic Chemistry, 2001, vol. 66, # 20, p. 6775 - 6786
[2] Tetrahedron Letters, 2001, vol. 42, # 29, p. 4841 - 4844
[3] Organic Letters, 2004, vol. 6, # 12, p. 1887 - 1890
[4] Dalton Transactions, 2017, vol. 46, # 18, p. 5955 - 5964
[5] Patent: US2009/82573, 2009, A1. Location in patent: Page/Page column 15