Indole-3-carboxylate ester

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. 

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). 

In the presence of tetracyanoethylene (TCNE), photocyclization of 2-azido-biphenyi gives carbazole as the main product, but an appreciable amount of a spiroazepine is also formed. Reviews of the chemistry [3746] of TCNE and of its use in cycloadditions [3244] are available. The synthesis of an indole by thermolysis of a previously prepared side-chain azide (see p. 301) is a widely used method but such an azide may also be formed in situ, as in this conversion of a benzaldehyde to an indole-2-carboxylic ester. 

Indole-2-carboxylic esters.- Benzs he mates followed by addition of alkyl oxalau indole-2-carboxylic ester synthesis on treain... 

The 3,4-disubstituted indole-2-carboxylate ester 45, which is encountered as part of the antibiotic nosiheptide, was obtained starting with the condensation of aniline 43 with benzyl 2-oxobutanoate. After protection of the hydroxyl group, Heck cyclization occurred in 46% yield. <94SL761>... 

In addition to direct formation from an arylhydrazine and a carbonyl compound, iV-aryl-hydrazones can be prepared from aryldiazonium ions by coupling with enolates or enamines (Japp-Klingemann reaction). This reaction has most frequently been applied to j -ketoesters. The coupling product undergoes deacylation so that the ultimate product of Fischer cycUzation is an indole-2-carboxylate ester (Scheme 58) <92JMC4823>. 

In 1999, Mederski s group [93] at Merck preclinic2il pharmaceutical research published an account on the application of this method for the synthesis of Af-aryl-substituted pyrrole- and indole-2-carboxylic esters. These intermediates were important for the synthesis of factor Xa antagonists. 

Scheme 6.6 Conversion of alkyl 2-azidocinnamates into indole-2-carboxylic esters ...

CuI/L-proline-catalyzed coupling of 2-halotrifluoroacetanilides 187 with pyrrole-2-carboxylate esters 188 in dimethyl sulfoxide (DMSO) at 80-90°C followed by in situ hydrolysis and condensative cyclization at60°C affordedpyrrolo[l,2-a]quinoxalines 189 with good yields (Scheme 66) [111]. Indole-2-carboxylate esters underwent the same process smoothly to provide the corresponding tetracychc products. 

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