Indole carboxylic acids, decarboxylation

XXXVIII), which on hydrolysis gave the indole carboxylic acid XXXIX. Decarboxylation of XXXIX then gave tryptamine. 

Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4//-pyrido-[l,2-u]pyrimidin-4-ones 289 by heating in 85% phosphoric acid, or in PPA yielded 7,12-dihydropyrimido[l, 2 l,2]pyrido[3,4-Z)]indol-4(6//)-ones 290 (96JHC799, 99MI12, 00MI22). From the 3-ester and 3-carboxylic acid derivatives 289 (R = COOEt, COOH) and decarboxylated products 290 (R = H) were obtained. 

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. 

SYNTHESIS A solution of 0.67 g 5-hydroxyindole (indol-5-ol) in 10 ml dry MeOH was treated with a solution of 0.30 g NaOMe in MeOH, followed by 0.70 g benzyl chloride. The mixture was heated on the steam bath for 0.5 h, and the solvent removed under vacuum. The residue was suspended between H20 and CH2CI2, the organic phase separated and the aqueous phase extracted once with CH2CI2. The combined organics were stripped of solvent under vacuum, and the residue distilled. A colorless fraction came over at 170-190 °C and spontaneously crystallized in the receiver. There was obtained 0.90 g (80%) 5-benzyloxyindole with a mp 81-86 °C which increased, on recrystallization from toluene / hexane, to 94-96 °C. A sample prepared from the decarboxylation of 5-benzyloxyindole-2-carboxylic acid has been reported to have a mp of 102 °C from benzene. 

Almotriptan has also been synthesized via decarboxylation of the carboxylic acid intermediate 65, but a detailed preparation of 65 was not provided in the patent literature (Scheme 22)." The patent indicates that the carboxy indole 65 was prepared according to the method of Gonzalez.°° Thus, (2-oxo-tetrahydro-3-furanyl)-glyoxylic acid ethyl ester (62) was heated in aqueous H2SO4 to give 2-oxo-5-hydroxypentanoic acid in situ, which was treated with hydrazine 59 to produce hydrazone 63. Fischer cyclization of 63 using HCl gas in DMF gave the lactone 64, which was converted to carboxylic acid 65. Decarboxylation of 65 was catalyzed by cuprous oxide in quinoline at 190 °C to afford almotriptan (5)." ... 

Dimethylindole was obtained from phenylhydrazine and butan-2-one, by a one-pot reaction in water (Scheme 9.10, Eq. 1). This is the first example of water as the reaction medium for Fischer indole synthesis, and significantly neither a preformed hydrazone nor addition of acid was required. Also, the decarboxylation of indole-2-carboxylic acid to afford indole is not trivial by traditional methods. However, in water... 

Jones, G.B. and Chapman, B.J., Decarboxylation of indole-2-carboxylic acids improved procedures, J. Org. 

Indole-2-carboxylic acid, 3-methyl-ethyl ester chlorination, 4, 215 Indolecarboxylic acids decarboxylation, 4, 286 esterification, 4, 287 Indole-2-carboxylic acids esters... 

Another general application is the decarboxylation of compounds related to pyrrole-2-carboxylic acid, such indole-2-carboxylic acid. The observed decarboxylation by microwave irradiation could simply result from the addition of water to the carboxyl group.76 78... 

Many compounds will undergo dimerization reactions those containing thiols (e.g., disulfide formation) olefins, alcohols, and carboxylic acids (or other carbonyl chemistry e.g., aldol condensation reactions). Indoles have been shown to dimerize under acidic conditions. The dimerization is presumed to occur as shown in Figure 120 via protonation at C3 and nucleophilic attack of a second indole on C2. Phenols have been shown to dimerize under free radical initiated oxidative conditions, usually to ortho phenols. Nalidixic acid API undergoes dimerization under thermolysis conditions to decarboxylate and produce a dimeric structure (Fig. 121) (172). 

Scheme 20 Formation of 2,3-dimethylindole and decarboxylation of indole-2-carboxylic acid in water [77]...

The Martinet procedure for the synthesis of indole-2,3-diones involves the reaction of an aminoaromatic compound and either an oxomalonate ester or its hydrate in the presence of an acid to yield a 3-(3-hydroxy-2-oxindole)carboxylic acid derivative which after oxidative decarboxylation yields the respective isatin. This method was applied with success for the synthesis of 5,6-dimethoxyisatin from 4-aminoveratrole whereas the use of 2,4-dimethoxyaniline was less successful40 (Scheme 9). 

Decarbonylation decarboxylation. At 110-170° this complex in catalytic amounts effects decarbonylation of simple aldehydes in quantitative yield.- Decarbonylation of typical indole-2-carboxaldehydes with in j/ M-generated catalyst proceeds in 82-95% yield. In fact, decarboxylation of some indole-2-carboxylic acids can be effected in higher overall yield by conversion to the aldehyde (LiAlH4 MnO,) followed by decarbonylation than by copp)er-catalyzed decarboxylation. ... 

Heterocyclic compounds containing a nitrogen atom commonly undergo N-alkylation or C-alkylation. N-Methyl pyrrole can be prepared by interaction of methyl iodide with potassium pyrrole (40%). N-Carbethoxy pyrrole is made from chloroformic ester and potassium pyrrole. The C-alkylation of pyrroles has been discussed. 3-Alkylindoles are made by the alkylation and decarboxylation of indole-2-carboxylic acid. The conditions for alkylation of pyrrolidine are analogous to those employed for the alkylation of a secondary amine. Thus, pyrrolidine on treatment with n-butyl bromide and potassium hydroxide in boiling benzene is con-... 

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