Madelung synthesis

Madelung indole synthesis
Named after	Walter Madelung
Reaction type	Ring forming reaction
Identifiers
RSC ontology ID	RXNO:0000511

In

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.

Overall reaction

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. A detailed reaction mechanism for the Madelung synthesis follows.

Reaction mechanism

The reaction begins with the extraction of a

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.

Advancements in improving reaction conditions

Various techniques have been applied to increase the yield of the desired

However, when the R5 substituent is an electron-withdrawing substituent, the yield is increased instead of decreased. Additionally, the efficiency of the reaction is also heavily dependent on the bulkiness of the R6 substituent. The bulkier this group, the less efficient is the reaction. The conditions required for the Madelung synthesis are quite severe. 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. For example, when electron-donating are placed on the aromatic ring of the N-phenylamide and an electron-withdrawing substituent is substituted at R5, the required temperature for the reaction decreases to approximately 25 °C.

butyl lithium (BuLi) and lithium diisopropylamide (LDA) bases are used, and when tetrahydrofuran is used as the solvent.^[2] This particular modification, the use of either of these metal-mediated bases, is termed the Madelung-Houlihan variation.^[3]

Synthetic applications

The Madelung synthesis has many important applications in chemistry, biochemistry, and industrial chemistry. 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. Nonetheless, the synthesis of such a complex molecule was, by itself, an incredible feat.

Another facet through which the Madelung synthesis has served useful is in the synthesis of 2,6-diphenyl-1,5-diaza-1,5-dihydro-s-

that may have important applications for low-cost light displays in commercial industry.

The Smith-modified Madelung synthesis

The Smith-modified Madelung synthesis, also called the Smith indole synthesis, was discovered in 1986 by Amos Smith and his research team. This synthesis employs a condensation reaction of organolithium reagents derived from 2-alkyl-N-

to 2-substituted indoles. The Smith indole synthesis is one of the most important modifications to the Madelung synthesis.

Reaction mechanism of the Smith indole synthesis

The Smith indole synthesis begins by use of two equivalents of an organolithium reagent (as organolithium reagents are very strong bases) to extract a hydrogen from both the alkyl substituent and the nitrogen, resulting in a negative charge on both. The synthesis proceeds with a nucleophilic attack of the carbanion on the electrophilic carbonyl carbon of the ester or carboxylic acid. When this occurs, the pi-bond of the electrophile is converted into a lone pair on the oxygen. These lone pairs are then reconverted back into a pi-bond, resulting in the expulsion of the -OR group. Next, the negatively charged nitrogen performs a nucleophilic attack on the adjacent electrophilic carbonyl carbon, again causing the pi-bond of the electrophile to be converted into a lone pair on the oxygen. This negatively charged oxygen then performs a nucleophilic attack on the silicon atom of the trimethylsilyl (TMS) group, resulting in a tricyclic compound, and a positively charged silicon atom and neutral oxygen atom. 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. Then, keto-enol tautomerism occurs, resulting in the desired product.

References