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7 CATEGORY Uac CYCLIZATIONS
7.1.5 Anomalous reactions
Anomalous Fischer cyclizations are observed with certain o-substituted aryl-hydrazones, especially 2-alkoxy derivatives[l]. The products which are formed can generally be accounted for by an intermediate which would be formed by ipso-substitution during the sigmatropic rearrangement step. Nucleophiles from the reaction medium, e.g. Cl' or the solvent, are introduced at the 5-and/or 6-position of the indole ring. Even carbon nucleophiles, e.g. ethyl acetoacetate, can be incorporated if added to the reaction solution. The use of 2-tosyloxy or 2-trifluoromethanesulfonyloxy derivatives has been found to avoid this complication and has proved useful in the preparation of 7-oxygen-ated indoles.
/pso-Substitution has also been observed with alkyl and aryl substituents and can lead to substituent migration. For example, 4-substituted indoles have been isolated from the cyclization of o-methyl and o-phenylphenylhydrazones of ethyl pyruvate. Formation of these by-products can be minimized by variation of the cyclization conditions and the use of p-toluenesulfonic acid in benzene or acetic acid was the preferred system,
Similarly, the iV-mesitylhydrazone of acetophenone gives 2-phenyl-4,5,7-trimethylindole as a minor product (10%), 2,4,6-Trialkylphenylhydrazones have also been observed to give 5,6,7-trialkylindoles as the result of a formal 3a -► 6 shift. These reactions probably occur via a 1,5-shift followed by a 1,2-shift.
_ CH3 C02C2H5
7.1 FISCHER INDOLE SYNTHESIS
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7.1.6 The Japp-Klingemann route to arylhydrazones
The Japp-Klingemann coupling of aryldiazonium ions with enolates and other nudeophilic alkenes provides an alternative route to arylhydrazones. The reaction has most frequently been applied to P-ketoesters, in which deacylation follows coupling and the indolization affords an indole-2-carboxylate ester.
и ,CH2R x-Й- 'I co2R'
ArN2+ + R"CCHC02R' -*■ ArNHN=C
If, instead of an ester, the Japp-Klingemann reaction is done with a salt of a [5-ketoacid, decarboxylation occurs and the eventual product is a 2-acyl-indole.
9 ch2r ri^v4v
ArN2~ + '°2CCHCR' -► ArNHN=C -► ' SR'
CH2R nR i
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