2-Methyl-2-butene → 1H-Indole-3-carboxylic acid, 2-chloro-

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Reaction Conditions

Reaction Steps

A mechanically stirred suspension of 15 g (83.5 mmol) of 2-chloroindole-3-carboxaldehyde [XXVI: R1 =R3 =H, X=Cl] (Schule, et al., Arch, Pharm. [Weinheim] 1972;305:523-533), 84 mL of 2-methyl-2-butene, and 200 mL of p-dioxane in an ice bath was treated with a solution of 40 g each of sodium chlorite and sodium dihydrogen phosphate monohydrate in 200 mL of water. The biphasic mixture was then stirred vigorously at 25° C. for 3.5 hours. An additional 16 g each of solid sodium chlorite and sodium dihydrogen phosphate monohydrate was added and the mixture was stirred for another 3.5 hours. The mixture was diluted with 350 mL of ethyl acetate and 200 mL of water. The layers were separated and the aqueous phase was extracted with 300 mL of ethyl acetate. The combined organic extracts were extracted with cold 2% aqueous NaOH (3×200 mL). The basic extracts were combined and acidified to pH 4 with 6N aqueous HCl. The precipitated solids were collected by filtration, washed well with water, and air dried overnight. The solids were dissolved in 150 mL of hot acetone and the solution was treated with 65 mL of hexane. After storage at 3° C. for 20 hours, the solids were collected by filtration, washed with cold acetone, and dried to leave 7.71 g of pure 2-chloroindole-3-carboxylic acid [XXVII: R1 =R3 =H, X=Cl] as an off-white solid; mp 181.5° C. (dec). Further processing of the filtrate as above afforded 2.41 g of a second crop; mp 179.5° C. (dec). Total yield 10.12 g (62%).

Provenance & Evidence