2-Pyridinecarboxylic acid, 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxy-, ethyl ester → HCID 131731316, compound

Participants

Reaction Steps

Synthesis of ethyl 4-(4-chloro-1H-imidazol-1-yl)-6-methoxypyridine-2-carboxylate (C34). 1,1-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (49.8 mg, 0.068 mmol) was added to a solution of ethyl 5-bromo-6-methoxypyridine-2-carboxylate (prepared in analogous fashion to methyl 5-bromo-6-methoxypyridine-2-carboxylate (C30) in Preparation 10; 254 mg, 0.97 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (264 mg, 1.17 mmol), and potassium acetate (293 mg, 2.92 mmol) in 1,4-dioxane (8 mL). The reaction was stirred at 85° C. for 6 hours, whereupon it was allowed to cool to room temperature. Dichloromethane was added, and the resulting mixture was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo to afford intermediate ethyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxypyridine-2-carboxylate. To a solution of ethyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxypyridine-2-carboxylate (crude) in methanol (50 mL) was added 4-chloro-1H-imidazole (C33) (100 mg, 0.97 mmol) and copper(I) oxide (14 mg, 0.098 mmol) and the reaction was stirred at ambient temperature overnight. The mixture was heated to 50° C. for 2 hours, and additional copper(I) oxide (14 mg, 0.098 mmol) was added. The reaction was heated to reflux for 2 hours and was then filtered through Celite. The Celite pad was washed with methanol, and the combined filtrate and washings were concentrated in vacuo. Purification was carried out twice via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane, then 0% to 40% ethyl acetate in heptane), affording the title compound as a white solid. Yield: 29.3 mg, 0.104 mmol, 11%. LCMS m/z 282.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.44 (t, J=7.1 Hz, 3H), 4.14 (s, 3H), 4.46 (q, J=7.1 Hz, 2H), 7.24 (d, J=1.6 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.82-7.83 (m, 1H), 7.84 (d, J=7.8 Hz, 1H).

Provenance & Evidence