Madelung synthesis

The Madelung indole synthesis, which is also referred to as the Madelung synthesis, Madelung reaction or Madelung cyclization, is a name reaction in organic chemistry. It was named after the German chemist Walter Madelung (1879-1963), who published the reaction in 1912. The reaction allows the synthesis of indole derivatives of ortho -alkyl-N - acylanilinen.

Overview reaction

Is ortho- alkyl-N- acylanilines set at high temperatures with a strong base (for example, potassium alkoxides ) in a way, formed under dehydration indole derivatives.

In place of potassium alcoholates and bases such as sodium amide or alkyl - and aryllithium can (such as butyllithium ) can be used. In the first case the required temperature is already significantly lower and in the reaction with butyllithium, the reaction can even be carried out at room temperature.

Mechanism

The mechanism of the Madelung indole synthesis is an example of the reaction of N-( 2-methylphenyl ) acetamide (1 ) is shown here with ethoxide as the base:

First deprotonated the base (here, ethanolate ) the nitrogen of the N-(2 -methylphenyl) acetamide (1). The anion thus formed is a 1.3 - 2 proton shift instead to form the carbanion 3 now uses This intramolecular the carbon atom of the carbonyl group, and thus forms a heterocyclic intermediate 4 which upon protonation gives alcohol 5, the elimination of water and formation of a C = C double bond leads to the indole 6, here 2-methyl -1H -indole.

This method is suitable to unsubstituted indole or in position to produce 2 -substituted indoles. On the other hand, difficulties arise in the synthesis of halogen-substituted indoles.