Indole Carboxylic Acids

Both indole-3-carboxylic and indol-2-ylacetic acids are easily decarboxylated in boiling water. In each case carbon dioxide is lost from a small concentration of / -protonated 3//-indolium cation, the loss, in each case, being analogous to the decarboxylation of a /3-keto-acid. Indole-1-carboxylic acid also decarboxylates very easily but is sufficiently stable to allow isolation and use in acylation reactions. Indole-2-carboxylic acids can only be decarboxylated by heating in mineral acid or in the presence of copper salts.  

Trifluoroacetylindoles are useful stable equivalents of acid chlorides, giving amides or acids in haloform reactions with lithium amides or aqueous base respectively. The reactivity of the A -hydrogen compounds is greater than of those with A -alkyl, indicating the intermediacy of a ketene in the reactions of the former.  

In a nice exemplification of the mesomeric interaction between indole nitrogen and a 3-carbonyl which renders the 3-carbonyl somewhat amide-like (see also 17.12), 2,3-dicarboxylic acid anhydrides react selectively with some nucleophiles at the 2-carbonyl inductive withdrawal by the ring nitrogen may also play a part in achieving this selectivity. 

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Flash vacuum pyrolysis of 2-methoxycarbonylpyrrole (11) gives the ketene (12), characterized by IR absorption at 2110 cm. On warming to -100 to -90 °C the dimer (13) is formed (82CC360). Flash vacuum pyrolysis of indole-2-carboxylic acid (14) results in loss of water and the formation of a ketene (15) showing absorption at 2106 cm (82CC360). 

Indole-2-carboxylic acid, 3-(arylazo)-ethyl ester... 

Indole-2-carboxylic acid, 5-bromo-l-hydroxy-tautomerism, 4, 197-198 Indolecarboxylic acid chloride synthesis, 4, 288... 

Cj HigNa, isolated as the picrate, m.p. 203-5-205-5°. From the acid products of the fusion indole-2-carboxylic acid was isolated. 

Rauwolscine gives colour reactions like those of yohimbine and the absorption curves of the hydrochlorides of the two alkaloids are very similar. Heated to 300°/5 mm. rauwolscinic acid forms barman (p. 490) and 3-ethylindole and on fusion with potassium hydroxide decomposes into indole-2-carboxylic acid, isophthalic acid, barman and an unidentified indole derivative. Rauwolscine itself on distillation with zinc dust produces barman, 2-methylindole (scatole) and tsoquinoline. It is suggested that the alkaloid has the skeletal strueture suggested by Seholz (formula XIV, p. 508) for yohimbine, the positions of the hydroxyl and earbomethoxy grouf s being still imdetermined. 

The first indolization of an arylhydrazone was reported in 1983 by Fischer and Jourdan" by treatment of pyruvic acid 1-methylphenylhydrazone 3 with alcoholic hydrogen chloride. However, it was not until the following year that Fischer and Hess identified the product from this reaction as 1-methyl indole-2-carboxylic acid 4. 

The Reissert procedure involves base-catalyzed condensation of an o-nitrotoluene derivative 1 with an ethyl oxalate (2) which is followed by reductive cyclization to an indole-2-carboxylic acid derivative 4, as illustrated below . ... 

In 1897, Reissert reported the synthesis of a variety of substituted indoles from o-nitrotoluene derivatives. Condensation of o-nitrotoluene (5) with diethyl oxalate (2) in the presense of sodium ethoxide afforded ethyl o-nitrophenylpyruvate (6). After hydrolysis of the ester, the free acid, o-nitrophenylpyruvic acid (7), was reduced with zinc in acetic acid to the intermediate, o-aminophenylpyruvic acid (8), which underwent cyclization with loss of water under the conditions of reduction to furnish the indole-2-carboxylic acid (9). When the indole-2-carboxylic acid (9) was heated above its melting point, carbon dioxide was evolved with concomitant formation of the indole (10). 

Under basic conditions, the o-nitrotoluene (5) undergoes condensation with ethyl oxalate (2) to provide the a-ketoester 6. After hydrolysis of the ester functional group, the nitro moiety in 7 is then reduced to an amino function, which reacts with the carbonyl group to provide the cyclized intermediate 13. Aromatization of 13 by loss of water gives the indole-2-carboxylic acid (9). 

This concept has also been applied to the acid-base equilibria of indole-2-carboxylic acids (15) and of coumarilic acids (16) and to the rates of saponification of their ethyl esters. The data were excellently... 

Indole, 1-methyl-, 40, 68 Indole-3-carbonttrile, 43, 58 Indoie-3-carboxaldehyde, conversion to indole-3-carbonitrile, 43, 58 Indole-2-carboxylic acid, ethyl ester, 43, 40... 

C jH2,NOSi) see Indanorex (lS-cii)-2,3-dihydro-l//-indene-l,2-diol (G7H10O2 6752S-22-7) see Indinavir sulfate (laS)-la,6a-dihydro-6//-indenori,2-6]oxirene (CgHjO 67528-26-1) see Indinavir sulfate (2,3-dihydro-l//-inden-4-yl)carbamimidothioic acid methyl ester monohydriodide (C, H 1N2S 40507-77-5) see Indanazoline 23-dibydro-l//-indole-2-carboxylic acid ethyl ester (C iH, N02 50501-07-0) see Perindopril... 

CjiHiyN iO . 9/022-35-0) see Mosapramine (25, 3a/f,7a5)>octahydro-l//-indole-2-carboxylic acid (C9H15NO2 145438-94-4) see Trandolapril (25,3a5 7a5)-octahydroindole-2-carboxylic acid (CyHi,N02 80875-98-5) see Perindopril [2S-(2a,3aa,7aP)]-octahydro-l/f-indole-2-carboxylic acid phenylmethyl ester... 

Indole 2-carboxylic acids can be readily decarboxylated to afford an indole. Hence, using pyruvic acid as an aldehyde equivalent in the coupling with 24 gave... 

Interestingly, the Fischer indole synthesis does not easily proceed from acetaldehyde to afford indole. Usually, indole-2-carboxylic acid is prepared from phenylhydrazine with a pyruvate ester followed by hydrolysis. Traditional methods for decarboxylation of indole-2-carboxylic acid to form indole are not environmentally benign. They include pyrolysis or heating with copper-bronze powder, copper(I) chloride, copper chromite, copper acetate or copper(II) oxide, in for example, heat-transfer oils, glycerol, quinoline or 2-benzylpyridine. Decomposition of the product during lengthy thermolysis or purification affects the yields. 

ICS 205-930 = (3-tropanyl)-IH-indole-2-carboxylic acid ester DOM = 2,5-dimethoxy-4-dimethylbenzene ethamine... 

Arylthioindole-2-carboxylic acids 303, obtained from aryl disulfides and indole-2-carboxylic acids, afford tetracyclic 5H-indolo-[3,2-fc][l,5]benzothiazepin-6(7H)-ones 304 on treatment with EDC-DMAP (Scheme 65 (1998MI139)). 

In terms of A -substitution, Hartwig reported improved conditions for the Pd(0) catalyzed N-arylation of indoles and pyrrole <99JOC5575>. It was found that when commercially available P(<-Bu)3 was employed as ligand and cesium carbonate as base, the reaction between indoles 95 and unhindered aryl bromides 96 or chlorides occurred under milder conditions than the Pd(OAc)2/DPPF system previously reported yielding the A/-arylated products 97. Alternatively, it has been found that pyrrole- and indole-2-carboxylic acid esters can be selectively 7V-arylated with phenylboronic acids in the presence of cupric acetate and either tiiethylamine or pyridine <99T12757>. 

Therefore better methods for the chiral reduction of indole-2-carboxylic acid derivatives would provide an elegant synthesis of this intermediate. A study by Kuwano and Kashiwabara of the reduction of indole derivatives into the corresponding indohnes found that a range of the more common ligand systems gave almost no enantioselectivity but the TRAP ligand gave the chiral indolines in up to 95 % ee for reduction of the methyl ester (B, R=Me, R =H). Further developments are awaited. 

The susceptibility of the indole ring towards electrophilic attack has also been exploited by Merour in the annulation of a coumarin unit to the indole ring. The heating of the o-bromophenyl ester of indole-2-carboxylic acid in the presence of a palladium-triphenylphosphine catalyst led to the formation of the tetracyclic product in 66% yield (4.32.)40... 

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