Madelung synthesis

In organic chemistry, 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.

Common reaction conditions include use of sodium or potassium alkoxide as base in hexane or tetrahydrofuran solvents, at temperatures ranging between 200–400 °C.

Variants with other bases or additional substituents are possible, but the method is essentially confined to the preparation of 2-alkinylindoles (not easily accessible through electrophilic aromatic substitution) because of vigorous reaction conditions.

Fortunately, the aforementioned modifications have been since applied to enhance its practicality, working to decrease the required temperature at which the reaction is performed and increase the desired product yield.

This reaction served useful in synthesizing, with an 81% yield, the architecturally complex tremorgenic indole alkaloid (-)-penitrem D, a molecule naturally produced by ergot fungus that causes various muscular and neurological diseases in livestock.

[4] Because this toxin ultimately causes significant economic problems in the livestock industry, understanding how to synthesize and easily decompose alkaloid (-)-penitrem D is of great importance.

This synthesis employs a condensation reaction of organolithium reagents derived from 2-alkyl-N-trimethylsilyl anilines by esters or carboxylic acids to yield substituted indoles.

[6] This synthesis has proven applicable to a wide variety of substituted anilines, including those with alkyl, methoxy, and halide groups, and can react with non-enolizable esters or lactones to yield N-lithioketamine intermediates.

The synthesis proceeds through an intramolecular heteroatom Peterson olefination, ultimately resulting in an elimination reaction which expels a TMSO group and forms a pi-bond in the five-membered ring at the nitrogen atom.