Indole-3-carboxylic esters

The reduced electrophUicity of indole-3-carboxylic esters (they are vinylogous carbamates) means that they are much more versatile directors of lateral lithiation than the comparable benzoates, as illustrated by the synthesis of 564 (Scheme 221... 

A procedure for obtaining indole-3-carboxylate ester from the f-pyrrolidino-o-nitrostyrene intermediates in the Leimgruber-Batcho indole synthesis was demonstrated. Although ethyl chloroformate is evidently not reactive enough, phosgene followed by methanolysis effects f) -carbomethoxylation. Reductive cyclization then gives the indole esters. <95SC95>... 

Irradiation of diazo quinoline 153 in alcohol provided the corresponding indole-3-carboxylic esters in 8-61% yield. Mechanistically, the transformation is a Wolff rearrangement and involves the formation of an intermediate carbene, ring contraction to ketene, and its solvolysis (76S754). 

X0- 13-dihydro-lH-indole-3-carboxylate ester 2-(Marylcarbamoyl)-2-diazoalkanoate ester 1924... 

Indole-3-carboxylate esters and 3-acetylindoles can be prepared by palladium-catalyzed cycli-zation of enamines (14). These can be prepared from the corresponding anilines by condensation with j8-dicarbonyl compounds or by palladium-catalyzed substitution reactions with ethyl acrylate or methyl vinyl ketone <86BCJ927, 90S215>. Overall yields for the two-step process are 60-80% (Scheme 33). 

In another example, arylhydroxyamines react with methyl propiolate to give indole-3-carboxylate esters <90H(3i)i43i>. When the hydroxyamine has no other nitrogen substituent, the product is substituted on nitrogen by an acrylate group derived from addition to methyl propiolate (Equation... 

Catalytic reduction of the nitro-epoxide (8.1, R = COOMe) leads directly to the indole carboxylic ester but when R = H, reduction of the nitro-epoxide does not give the indole. However, cleavage of the epoxide and reduction of the nitro group gives the amine (8.2) which is cyclized by a strong base. 

MeOCH=N Me2, which combines with the deprotonated aromatic. Both tris(piperidin-l-yl)methane and bis(dimethylamino)-r-butoxymethane are said to function even better than the commercially available DMFDMA. A variety of benzene substituents are tolerated and the approach has been utilised for syntheses of, amongst others, 4- and 7-indole-carboxylic esters. 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

Preparation of indole-2-carboxylate esters by the Hemetsberger method... 

The Japp-Klingeraann coupling of aryidiazonium ions with enolates and other nucleophilic alkenes provides an alternative route to arylhydrazones. The reaction has most frequently been applied to P-ketoesters, in which deacylation follow S coupling and the indolization affords an indole-2-carboxylate ester. 

Lewis acids such as zinc triflate[16] and BF3[17] have been used to effect the reaction of indole with jV-proiected aziridine-2-carboxylate esters. These alkylations by aziridines constitute a potential method for the enantioselective introduction of tryptophan side-chains in a single step. (See Chapter 13 for other methods of synthesis of tryptophans.)... 

A solution of trifluoroacetic acid in toluene was found to be advantageous for cyclization of pyruvate hydrazoncs having nitro substituents[4], p-Toluene-sulfonic acid or Amberlyst-15 in toluene has also been found to give excellent results in preparation of indole-2-carboxylate esters from pyruvate hydra-zones[5,6J. Acidic zeolite catalysts have been used with xylene as a solvent to convert phenylhydrazines and ketones to indoles both in one-flask procedures and in a flow-through reactor[7]. 

Indole-2-carboxylic esters undergo reduction with magnesium in methanol to give the related indoline (86TL2409). 

The presence of an electron-withdrawing substituent on the five-membered ring of the indole system generally deactivates that ring to electrophilic attack by both elemental bromine and A-bromosuccinimide. Thus, ethyl indole-3-carboxylate and 3-formylindole are brominated on the benzenoid ring (72HC(25-2)127,79HC(25-3)357). The 2-carboxylic ester, however, yields the 3,5-dibromo derivative. 

Halogenomethylpyrroles have been oxidized with lead(IV) salts or by chromium trioxide to yield the formylpyrroles, whilst catalytic hydrogenolysis or zinc-acetic acid reduction produces the 2-methylpyrroles (B-77MI30504). The methyl derivatives are also obtained by hydride reduction of trifluoromethyl-pyrroles and -indoles, and trifluoromethylindoles are converted into the carboxylic esters by ethanol under basic conditions (74JOC1836). 

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 reaction of MP with 1-methyl- and l-phenyl-2-vinylpyrrole 20a,b afforded 1-substituted indole-4,7-dicarboxylie esters 27 via a further [4 + 2]-cycloaddition to the initially formed 6,7-dihydroindole-4-carboxylic ester 26 by a second molecule of MP, followed by a retro-Diels-Alder extrusion of ethene (80JOC4515). Maximum yields were obtained with 2 1 ratio of MP to vinylpyrrole. The intermediate adduct 26 could not be isolated and when the reaction was monitored by NMR spectroscopy, signals attributable to the dihydroindole-4-carboxylic ester 26 were of very low intensity, suggesting that the second and third steps of the reaction sequence were either comparable in rate or faster than the initial cycloaddition step. 

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