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

Temperature

0 °C

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).

1. temperatureThe solution was cooled to −78° C.
2. stirringThe resulting mixture was stirred vigorously at −78° C. for 30 min
3. temperaturewarmed to 0° C. for 1 h
4. customThe reaction flask was evacuated
5. additionback-filled with N2 (3×)
6. temperaturethen heated to 65° C
7. waitAfter 20 h
8. customthe reaction was removed
9. temperaturefrom heat
10. customquenched with saturated aqueous ammonium chloride
11. customThe biphasic mixture was transferred to a separation funnel
12. extractionextracted with EtOAc (3×)
13. washThe combined organics were washed with 1M Na2S2O3, saturated aqueous sodium bicarbonate, water, and brine
14. dry with materialdried over MgSO4
15. filtrationfiltered
16. concentrationconcentrated
17. customto get crude product
18. customPurified on Biotage 40S column
19. washeluting with 0-20% EtOAc/heptane

ORD record

ord-efbeb7ecd4a243dea08a40e0cbf24639

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09056865B2