Synthesis
A heptane (200 mL) solution of 2-(dimethylamino)ethanol (4.79 mL, 47.8 mmol) was stirred in an ice bath under nitrogen protection. A hexane solution of butyl lithium (38.2 mL, 96 mmol) was slowly added via syringe and stirring was continued at low temperature for 30 minutes. Subsequently, 4-tert-butylpyridine (7.0 mL, 47.8 mmol) was slowly added via syringe and the reaction mixture was stirred at low temperature for 1 h to obtain an orange colored solution. The solution was transferred to an iPrOH/CO2 bath for cooling and a pre-cooled solution (ice-bath cooled) of fully bromomethane (19.02 g, 57.3 mmol) dissolved in heptane (200 mL) was added slowly via cannula. The brown, non-homogeneous reaction mixture formed was stirred at low temperature for 1 h, followed by slow warming to room temperature and stirring overnight. After completion of the reaction, the mixture was again cooled in an ice bath and quenched by careful addition of water. The mixture was extracted twice with ether, the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was adsorbed onto diatomaceous earth. Finally, the separation was carried out by column chromatography on a 300 g silica gel column using 10-20% EtOAc/heptane as eluent. A brown grade (10% EtOAc/heptane) with an Rf value of about 0.3 was collected to give 2.90 g of a brown oily product containing 2-bromo-4-tert-butylpyridine in 28% yield.
References
[1] Tetrahedron Letters, 2010, vol. 51, # 50, p. 6622 - 6625
[2] Journal of Organic Chemistry, 1983, vol. 48, # 22, p. 4156 - 4158
[3] Chemical Communications, 2009, # 41, p. 6270 - 6272
[4] Patent: US2011/230462, 2011, A1
[5] Patent: US9219237, 2015, B1
