2-Bromo-6-chloropyridine → 6'-Chloro-3,5-dimethyl-2,2'-bipyridine

Participants

Reaction Conditions

Reaction Steps

An oven-dried flask under N2 was charged with TMS-CH2Li (2.57 mmol, 1M in pentane) and cooled to 0° C. Then a solution of the 2-iodo-3,5-dimethylpyridine (300 mg, 1.29 mmol) in heptane (4.3 mL) was added dropwise, and the resulting mixture was stirred at 0° C. for 1 h. The solution was cooled to −78° C., and 2 mL THF was added. A solution of ZnBr2 (435 mg, 1.53 mmol) in THF (4.3 mL, cooled to 0° C.) was added dropwise. The resulting mixture was stirred vigorously at −78° C. for 30 min, then warmed to 0° C. for 1 h. Solid 2-bromo-6-chloropyridine (371 mg, 1.93 mmol) and Pd(PPh3)4 (74 mg, 5 mol %) were added. The reaction flask was evacuated and back-filled with N2 (3×) then heated to 65° C. After 20 h, the reaction was removed from heat and quenched with saturated aqueous ammonium chloride. The biphasic mixture was transferred to a separation funnel and extracted with EtOAc (3×). The combined organics were washed with 1M Na2S2O3, saturated aqueous sodium bicarbonate, water, and brine, then dried over MgSO4, filtered, and concentrated to get crude product. Purified on Biotage 40S column, eluting with 0-20% EtOAc/heptane to afford 166 mg (59%) of the title compound as an orange oil. LCMS and NMR showed desired product >95% pure. m/z (APCI+) for C12H11N2Cl=219.00 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (s, 1 H) 7.95-8.01 (m, 1 H) 7.88-7.94 (m, 1 H) 7.58 (s, 1 H) 7.53 (d, J=7.83 Hz, 1 H) 2.47 (s, 3 H) 2.33 (s, 3 H).

Provenance & Evidence