Carbon Dioxide → Methyl 2,6-dichloro-4-iodonicotinate

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Reaction Steps

A solution of n-butyllithium in hexane (1.6M, 120 mL, 192 mmol) was added dropwise to a solution of diisopropylamine (31.2 mL, 219 mmol) in THF (200 mL) at −78° C. and the mixture was stirred for 30 min. A solution of 2,6-dichloro-3-iodopyridine (50.0 g, 183 mmol) in THF (100 mL) was added dropwise to the reaction mixture at −78° C. and the resulting mixture was stirred at −78° C. for 2 h. After adding dry ice to the reaction mixture, the mixture was warmed to RT and stirred overnight. The resulting mixture was quenched with H2O and the organic phase was washed with H2O. The combined aqueous phase was acidified with HCl and extracted with CHCl3 (3×). The organic phases were combined, washed with brine, dried over MgSO4, and evaporated. After the residue was dissolved into DMF (500 mL), K2CO3 (39.2 g, 284 mmol) and CH3I (17.73 mL, 284 mmol) were added. The reaction mixture was stirred at RT for 3 h. To the resulting mixture was added 1N HCl and Et2O. The aqueous phase was extracted with Et2O and the combined organic layers were washed with H2O and brine, dried over MgSO4 and evaporated. The residue was purified by chromatography on SiO2 to give the title compound as a white solid (7.24 g, 11%). 1H NMR (500 MHz, CDCl3) δ ppm 3.99 (s, 3 H), 7.77 (s, 1H). [M+H] calc'd for C7H4Cl1NO2, 332; found, 332.

Provenance & Evidence