Indole 2- ethyl-, ring synthesis

A key intermediate for the synthesis of the indole alkaloid, vineamine, has been prepared by the anodic oxidation of l-earbomethoxy-3-ethyl-3-(P-carboxyethyl)-piperidine 33 in methanol. The regioselective methoxylation at the 2-position was not possible, instead the 6-position was also methoxylated. Thus, the starting material has been methoxylated at both 2- and 6-positions to give 34 and the methoxy group on the 6-position is eliminated during the formation of lactone ring at the 2-position24). 

Several syntheses are on record which avoid the preparation of 5-benzyloxyindole in these procedures, the indole ring is usually formed after provision is made for the introduction of the ethanamine side chain. The first of these (107, 108) was an adaptation of Ewins original trypt-amine synthesis. A subsequent route (109) started from ethyl a-cyano-2,5-dimethoxycinnamate (VIII), which was prepared by condensation of 2,5-dimethoxybenzaldehyde with ethyl cyanoacetate. When this was boiled with potassium cyanide solution, addition of the elements of hydrogen cyanide was accompanied by hydrolysis of the ester function and decarboxylation, to give 2,5-dimethoxyphenylsuccinonitrile (IX). 

This ring closure takes place readily whenever the carbonyl and amino groups occur in the relative positions shown above. Reduction of o-nitro-phenylacetonitrile by stannous chloride produces indole rather than the corresponding amino aldehyde. The synthesis is most useful for the preparation of indole-2-carboxylic acid by reduction of o-nitrophenyl-pyruvic acid with ferrous sulfate and ammonia or with sodium hydrosulfite. The ethyl ester is obtained by a similar reduction with zinc and acetic acid or by catalytic hydrogenation of ethyl o-nitrophenyl-pyruvate over platinum oxide catalyst. ... 

The Japp-Klingemann reaction was the key step during the first synthesis of the pentacyclic pyridoacridine marine cytotoxic alkaloid amoamine A by E. Delfoume et a P The diazonium salt was added to a vigorously stirred solution of ethyl-2-methyl-3-oxobutyrate in ethanol containing KOH, NaOAc and water. The resulting hydrazone was exposed to polyphosphoric acid to form the indole ring. 

Heterocyclic Synthesis. - The reactions of phosphorus ylides with phenan-threne-9,10-quinone (113) have been used to prepare phenanthrene [9,10-x]-fused compounds with four, five, and six membered heterocyclic rings. (E)-4-carbethoxymethylene-l,2,3,4-tetrahydro-2-quinolones 114 have been obtained from the stereoselective reaction of 3-hydroxy-1,2,3,4-tetrahydroquinoline-2,4-diones and ethyl(triphenylphosphoranylidene)acetate. A -trifluoroacetylanilines 115 react with Ph3P=C02Et producing enamine derivatives 116 as a mixture of (E)- and (Z)-isomers. Enamines 116 are useful precursors for the synthesis of indoles and quinolones. 

When the Fischer synthesis is applied to an unsymmetrical ketone, either one of two isomers or a mixture of them may be produced. (+)-3-MethylcycIopen-tanone gives a mixture of I- and 2-methylcyclopent[0]indoles, and the relative amounts of these formed under various conditions are analysed [3222]. Further work has recently been published on the Fischer indolization of -methoxy-phenyl- -phenylhydrazones of an unsymmetrical ketone (ethyl pyruvate). Cyclization in acid occurs mostly on to the more electron-rich benzene ring whereas under nonacidic (for example, thermal) conditions there is less regio-selectivity [3539]. 2-Methoxyphenylhydrazine sometimes behaves anomalously and does not yield the expected 7-methoxyindole, but when o-4-toluenesuIphonyl-or o-4-trifluoromethylsulphonyI-phenylhydrazine is used to prepare the hydra-zone, the main product is the 7-sulphonyloxyindole which may be hydrolysed to the 7-hydroxyindole with alkali [3629]. 

The key steps in this synthesis are the direct formation of the substituted indole ester (11) by the acid-catalysed reaction of ethyl pyruvate with methylphenylhyd-razine, the closure of the tetrahydro- -carboline ring by reaction of (11) with... 

---