Synthesis of Methyl 5- and 6-Nitroindole-2-carboxylates by Nitration of Indoline-2-carboxylic Acid

Abstract

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...

A Facile Chiral Pool Synthesis of (S)-6-Nitroindoline-2-carboxylic Acid from l-Phenylalanine

“…(S)-6-Nitroindoline-2-carboxylic acid (1) can easily be converted into other 6-substituted (S)-indoline-2-carboxylic acids that can be utilized in the synthesis of pharmaceuticals. 12 It can be obtained from the nitration of (S)-indoline-2-carboxylic acid; 13 however, this gives a mixture of 5-nitro and 6-nitro derivatives, which cannot be easily separated. 13 Moreover, few of the methods mentioned above are chiral pool methods.…”

“…12 It can be obtained from the nitration of (S)-indoline-2-carboxylic acid; 13 however, this gives a mixture of 5-nitro and 6-nitro derivatives, which cannot be easily separated. 13 Moreover, few of the methods mentioned above are chiral pool methods. L-Phenylalanine is a convenient chiral pool compound 14 due to its facile availability and, thus, it is widely used in the synthesis of natural and bioactive molecule.…”

“…: 3396 (s), 3113 (br s), 1727 (s), 1521 (s), 1335 cm -1 (s). 1 H NMR (400 MHz, DMSO-d 6 ): d = 12.84 (br s, 1 H, COOH), 7.43 (dd, J = 2.4, 8.0 Hz, 1 H, H5), 7.25 (d, J = 2.4 Hz, 1 H, H7), 7.22 (d, J = 8.0 Hz, 1 H, H4), 6.67 (s, 1 H, NH), 4.44 (dd, J = 5.6, 10.4 Hz, 1 H, CH),3.37 (ddd, J = 5.6, 10.8, 18.4 Hz, 2 H, CH 2 ) 13. C NMR (101 MHz, DMSO-d 6 ):d = 175.0, 152.9, 148.3, 135.6, 124.8, 113.1,, 60.1, 33.3.…”