Madelung synthesis

The Madelung synthesis is a chemical reaction that produces (substituted or unsubstituted) indoles by the intramolecular cyclization of N-phenylamides using strong base at high temperature.The Madelung synthesis was reported in 1912 by Walter Madelung, when he observed that 2-phenylindole was synthesized using N-benzoyl-o-toluidine and two equivalents of sodium ethoxide in a heated, airless, reaction. Common reaction conditions include use of sodium or potassium alkoxide as base in hexane or tetrahydrofuran solvents, at temperatures ranging between 200-400 °C. A hydrolysis step is also required in the synthesis. The Madelung synthesis is important because it is one of few known reactions that produce indoles from a base-catalyzed thermal cyclization of N-acyl-o-toluidines. The overall reaction for the Madelung synthesis follows.

This method is essentially confined to the preparation of 2-alkinylindoles (not easily accessible through electrophilic aromatic substitution) because of the vigorous reaction conditions. A detailed reaction mechanism for the Madelung synthesis follows.

The reaction begins with the extraction of a hydrogen from the nitrogen of the amide substituent and the extraction of a benzylic hydrogen from the substituent ortho to the amide substituent by a strong base. Next, the carbanion resulting from the benzylic hydrogen extraction performs a nucleophilic attack on the electrophilic carbonyl carbon of the amide group. When this occurs, the pi-bond of the amide is converted into a lone pair, creating a negatively charged oxygen. After these initial steps, strong base is no longer required and hydrolysis must occur. The negatively charged nitrogen is protonated to regain its neutral charge, and the oxygen is protonated twice to harbor a positive charge in order to become a good leaving group. A lone pair from the nitrogen forms a pi-bond to expel the positively charged leaving group, and also causes the nitrogen to harbor a positive charge. The final step of the reaction is an elimination reaction (specifically an E2 reaction), which involves the extraction of the other hydrogen that was once benzylic, before the bicyclic compound was formed, whose electrons are converted into a new pi-bond in the ring system. This allows the pi-bond formed by nitrogen in the preceding step to be converted back into a lone pair on nitrogen to restore nitrogen's neutral charge.

...
Wikipedia