Hemetsberger indole synthesis

What is Hemetsberger indole synthesis?

The synthesis of indole-2-carboxylic esters via the thermal decomposition of 3-aryl-2-azidopropenoic esters was first reported in 1969 by Hemetsberger and Knittel, et al. Hemetsberger indole synthesis has been given various names, such as Hemetsberger azide pyrolysis, Hemetsberger cyclization, Hemetsberger rearrangement, Hemetsberger-Rees styryl azide thermolysis, Hemetsberger-Knittel indole synthesis, Hemetsberger-Knittel reaction, and Hemetsberger synthesis. However, due to the instability and difficult accessibility of the starting material, this reaction has not been extensively explored.

Hemetsberger indole synthesis - general reaction scheme - Hemetsberger azide pyrolysis - Hemetsberger cyclization, Hemetsberger rearrangement - Hemetsberger-Rees styryl azide thermolysis - Hemetsberger-Knittel indole synthesis - Hemetsberger-Knittel reaction - Hemetsberger synthesis
Hemetsberger indole synthesis

R = Me, Et, etc. (see list of acronyms)

To prepare the starting materials for this reaction, aromatic aldehydes and methyl azidoacetate are typically condensed via the Claisen-Schmidt condensation.

For instance, the corresponding azidocinnamic ester can be prepared from 2-O-(1-methyl)hexyl-5-bromo 2-hydroxylbenzaldehyde by treatment with ethyl azidoacetate and sodium methoxide NaOMe in methanol MeOH. Subsequently, the thermal decomposition is carried out in refluxing xylene, resulting in highly regiospecific indole derivatives.

The synthesis of several indole alkaloids has been effectively achieved through this reaction.

References

Hemetsberger, H., Knittel, D., Weidmann, H., 1969. Synthese von α-Azidozimtsäureestern [Synthesis of α-azido cinnamic acid esters]. Monatshefte für Chemie, 100(5), 1599-1603
DOI: 10.1007/BF00900176

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