Indoline-2-carboxylic acid was transformed into 6-nitroindoline-2-carboxylic acid, the methyl ester of which was easily dehydrogenated by DDQ to methyl 6-nitroindole-2-carboxylate (total yield: 67%). Methyl 5-nitroindole-2-carboxylate was obtained by the nitration of methyl 1-acetylindoline-2-carboxylate acid followed by dehydrogenation with MnO 2 in toluene in 40% total yield. Key words: methyl 5-and 6-nitroindole-2-carboxylate, indolineindole method, indoles Nitroindole-2-carboxylic acids are the precursors of corresponding aminoindole carboxylic acids, which can be used as building blocks in the synthesis of analogs of the antibiotics containing carboxamide moieties (e.g. CC-1065, distamycin, and netropsin) capable of sequence selective DNA interaction. Whereas ethyl 5-nitroindole-2-carboxylate was obtained by Fischer indole synthesis from the 4-nitrophenylhydrazone of ethyl pyruvate in 50-60% yields, ethyl 6-nitroindole-2-carboxylate was obtained from the 3-nitrophenylhydrazone of ethyl pyruvate in 8% yield as a mixture with the 4-nitro isomer. 1-3 Methyl 4,5,6, and 7-nitroindole-2-carboxylates were also obtained by condensation of the corresponding nitrobenzaldehydes with methyl 2-azidoacetate followed by thermolysis. 4 Nitration of protonated indoline leads selectively to 6-nitroindoline, whereas nitration of 1-acetylindoline produces 1-acetyl-5-nitroindoline as protonated nitrogen gives meta-direction whereas the non-protonated N-acetyl group in indoline shows para-direction. 5 We used here this indoline-indole approach for the preparation of nitroderivatives of indole-2-carboxylic acid. Nitration of commercially available indoline-2-carboxylic acid with concentrated HNO 3 in concentrated H 2 SO 4 led to a mixture of 6-and 5-nitroindoline-2-carboxylic acids 2 and 5, in which the 6-nitro derivative 2 was the predominant compound (Scheme). Compound 5 admixed with 2 was extracted with EtOAc at pH < 2, then the aqueous phase was adjusted to pH 4.5-5.0 and extracted with EtOAc, to give 72% of pure 6-nitroindoline-2-carboxylic acid (2), which was esterified to give methyl 6-nitroindoline-2-carboxylate (3). Additional amounts of 3 (6%) and 6 (10%) were obtained after esterification of the products extracted from the reaction mixture at pH < 2, followed by column chromatography. Dehydrogenation of 3 proceeded under unexpectedly mild conditions (refluxing with DDQ in a EtOAc-benzene mixture) to give the target methyl 6-nitroindole-2-carboxylate (4) in 95% yield.For the preparation of methyl 5-nitroindole-2-carboxylate (7) we used methyl 1-acetylindoline-2-carboxylate (9), which was obtained by the acetylation of methyl indoline-2-carboxylate (8) (Scheme). Nitration of 9 in concentrated HNO 3 -Ac 2 O mixture gave methyl 1-acetyl-5-nitroindoline-2-carboxylate (10) (63% after column chromatography). Hydrolysis of 10 led to 5-nitroindoline-2-carboxylic acid, which was reesterified without isolation to give ester 6. All attempts to dehydrogenate compound 6 using DDQ under various conditions were unsuccessful, but reflux...
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