[Synthesis]
Racemic benzyloxycarbonyl-α-phosphonylglycine trimethyl ester (12.08 g, 36.5 mmol) was dissolved in 80 mL of dichloromethane at room temperature, and DBU (6.34 mL, 42.1 mmol) was slowly added. 30 min later, 20 drops of 2-chloro-3-formyl-4-iodopyridine (7.5 g, 28.0 mmol) was slowly added at the same temperature. mL of dichloromethane solution. The reaction was slightly exothermic during the dropwise addition and the temperature needed to be controlled by a cold water bath. After 4 hours of reaction, the reaction mixture was diluted with dichloromethane and washed sequentially with aqueous 1N hydrochloric acid (twice) and water (once). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by fast column chromatography (ISCO Redi-Sep 330 g silica gel, 20% ethyl acetate/hexane elution) afforded methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(2-chloro-4-iodo-pyridin-3-yl)prop-2-enoate (11.46 g, 86% yield) as a white solid.1H NMR (399 MHz, CDCl3 ) δ: 7.89 (d, J = 5.1 Hz, 1H), 7.70 (d, J = 5.1 Hz, 1H), 7.33 (m, 3H), 7.24 (m, 2H), 7.06 (s, 1H), 6.96 (s, 1H), 4.97 (s, 2H), 3.91 (s, 3H). Methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(2-chloro-4-iodopyridin-3-yl)prop-2-enoate (11.46 g, 24.25 mmol), potassium carbonate (10.05 g, 72.7 mmol), cuprous iodide (0.462 g, 2.425 mmol) and L-proline (0.558 g, 4.85 mmol) were mixed in 1,4-dioxane (120 mL). The mixture was degassed by three evacuations/nitrogen displacement and heated to reflux. After refluxing overnight, it was cooled to room temperature, diluted with saturated aqueous ammonium chloride solution and extracted with dichloromethane (3 times). The combined organic layers were dried over anhydrous magnesium sulfate, filtered through a diatomaceous earth pad and concentrated. The resulting solid was ground with ether/hexane to give methyl 4-chloro-5-azaindole-2-carboxylate (4.6 g, 90% yield) as an off-white solid.1H NMR (399 MHz, CDCl3) δ: 9.25 (s, 1H), 8.18 (d, J = 5.8 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 5.9 Hz, 1H), 3.99 (s, 3H). |