Indole-3-carboxylic acid derivatives

Scheme 20 Structure of indole-3-carboxylic acid derivatives (see Figures 9 and 10).

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 . ... 

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. 

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 Reimer-Tiemann reaction is not an effective route to formyl-pyrroles or -indoles (see Section 3.05.1.6) and the oxidation of alkyl and hydroxyalkyl derivatives of the heterocycles and the reduction of carboxylic acid derivatives are discussed in Sections 3.05.2.2 and 3.05.2.4, respectively. 

Pyrrole- and indole-carboxylic acid chlorides react with dialkyl- and diaryl-cadmium to yield the ketones and it is noteworthy that the reaction of the anhydride of indole-2,3-dicarboxylic acid with diphenylcadmium produces 3-benzoylindole-2-carboxylic acid and not its isomer (53JCS1889). The ability of l-methylindole-2-carboxylic acid to react with nucleophiles is enhanced by conversion into the mixed anhydride with methanesulfonic acid. The mixed anhydride reacts with carbanions derived from diethyl malonate and from methyl acetate to yield the indolyl (3- keto esters (80TL1957). 

The magnesium bromide salt of indole gives the 3-carboxy derivatives in about 30% yield on reaction with carbon dioxide (56JCS2853). Ethyl indole-3-carboxylate can be obtained directly, but in modest yield, using ethyl chloroformate (62JOC496, 6602805). Indole-2-carboxylic acid derivatives can be obtained via the benzenesulfonyl-protected 2-lithio derivative (equation 181) (73JOC3324). 

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). 

The position of the sugar residue in the dihydroindole portion can be determined by methylation of the pigment with diazomethane and subsequent alkaline degradation of the resulting neobetanin derivative. In the case of 5-0-glycosides, 5-hydroxy-6-methoxyindole-2-carboxylic acid is obtained, whereas the 6-O-glyco-sides yield 6-hydroxy-5-methoxyindole-2-carboxylic acid (47,48). The indole carboxylic acids are easily identified by TIjC. 

Now that we have got the hydrazone, the Fischer indole reaction is straightforward and gives i- indole-2-carboxylic acid derivative. There is only one site for the enamine, and the indole is forme away from the substituents already on the ring. 

For the retrosynthesis of indole (see Fig. 5.8), two routes (I/II) are proposed, as for pyrrole (see p 94). Route I suggests o-aminobenzyl ketone 1 or 6>-alkyl-A -acylaniline 2 as starting material on the basis of operations a - c. Their retroanalysis (d,e) in turn leads to 2-alkylaniline 5 and carboxylic acid derivative 6. Construction of the indole system should thus occur by N- or C-acylation of 5 (utilizing the o-nitrotoluene derivative 4) followed by cyclodehydration of 1/2. The alternative route n, based on retrosynthetic analysis g-i, leads to aniline via the a-(A -phenylamino)ketones 3 and to a-halo ketones 7 as possible precursors for the indole synthesis. 

Since strategies for the multistep synthesis of indole 1 and indole-2-carboxylic acid 2 are usually based on different schemes, a detailed discussion of the synthesis of compound 2 and related indole-2-carboxylic acid derivatives is covered separately in Section IIB2. 

Pyrrole and indole carbonitriles are readily prepared by dehydration of oximes. Because the aldehydes are easily available by Vilsmeier-Haack formylation, this represcarboxylic acid derivatives <80CJC409,88SC67l,93JMC10l>. 

Both 1-methylpyrrole and 1-methylindole can be easily lithiated and the resulting intermediates have been used extensively in synthesis. The range of electrophiles which can be used with lithiated pyrroles and indoles is quite broad. Aldehydes and ketones give carbinols. A,A-Disubstituted formamides give aldehydes. Carbon dioxide and alkyl chloroformates have been used to make carboxylic acid derivatives. Alkyl halides, sulfates and sulfonates can be used to introduce alkyl groups. Interestingly, even t-butyl bromide has been used successfully for alkylation (see entry 3, Table 7). Some examples are given in Table 7. 

Decarboxylation and oxidation products of 1,2,3,4-tetrahydro-P-carbohne-3-carboxylic acids derived from formaldehyde, 9H-pyrido(3,4-fo]indole (norharmane, 2-127), and acetaldehyde, 1-methyl-9//-pyrido[3,4-fo]indole (harmane, 2-127), were identified in a number of foods at levels up to 700 mg/kg, although more typically their concentrations in smoked, cooked and fermented foods range from a few mg/kg to 1-2 orders of magnitude less. Typical norharmane and harmane findings in pan-fried, minced meat, beef patties or ground beef prepared at temperatures of 175-230 °C and... 

A -Flnoropyridininm triflates 18 are another nsefnl type of fluorinating reagents applied for the preparation of fluorinated indoles. Using these reagents a series of 2-(3-fluoroindolyl)carboxylic acid derivatives 19 was prepared in good yields by treatment of indole-2-carboxylates or carboxamides 17 in dichloromethane [4, 9],... 

Fluorinated indoles reveal very similar properties in comparison to their non-fluorinated analogues. However, it should be noted that the chemistry of monofluori-nated indoles (with fluorine atom attached to both 2 and 3 position) is scarcely studied. For example, 3-fluoroindole derivative 19a was debenzylated to give indole carboxylic acid ester 157 quantitatively the latter one was converted into amide 159 by hydrolysis followed by reaction with the corresponding amine in the presence of BOP reagent [9a]. Nitrogen atom in case of 3-fluorosubstituted indole derivatives has usual nucleophilicity and can participate in standard indole reactions, for example reaction with tosyl chloride provided V-sulfonylation product in 61 % yield [15]. 

With the preliminary results in hand, it was crucial that the C2 group on the indole could be readily removed. The C2 carboxylic acid derivatives of coupling products were initially employed toward this endeavor (Scheme 4). There are relatively few decarboxylation methods on indole acids reported in the literature, most of which utilize harsh reaction conditions. Nevertheless, Jagan tested several of the reported methods, including the use of copper chromite in quinoline at 215 °C, copper(I)oxide in DMA at 200 °C, and substoichiometric amounts of indole acid copper salts at 200 Much to his dismay, most of these reactions led to decomposition. Moreover, adjusting temperature or switching to microwave heating failed to provide the desired decarboxylation. 

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