Iodine → 5-Chloro-3-[5-(5,5-dimethyl-[1,3]dioxan-2-yl)-2-methoxyphenyl]-3-hydroxy-1,3-dihydroindol-2-one

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Reaction Steps

Magnesium turnings (2.2 g, 89 mmol) were introduced into THF (30 ml) and etched with some iodine crystals. While stirring, a solution of 2-(3-bromo-4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane (26.0 g, 86 mmol) in THF (80 ml) was added thereto. After the reaction started (identifiable by the evolution of heat), the rate of dropwise addition was slowed down so that the reaction mixture just continued to boil. The reaction mixture was then stirred for 20 min and subsequently cooled to room temperature. The Grignard solution obtained in this way was pumped into an ice-cooled solution of 5-chloroisatin sodium salt [prepared by treating a solution of 5-chloroisatin (13.1 g, 72 mmol) in THF (400 ml) with one equivalent of sodium hydride at 0° C. for one h] and then stirred at room temperature for 5 hours. Aqueous ammonium chloride solution was added to the reaction solution while stirring, and the mixture was extracted twice with ethyl acetate. The combined organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The desired product crystallizes on treating the residue with diethyl ether. Yield: 19.2 g (66%) of a white solid. MS (API-ES, pos) m/z=386 [M+H—H2O]+

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