Madelung synthesis electrophiles

Another variation of the Madelung synthesis involves use of an O-alkyl or O-silyl imidate as the C2 electrophile. The mechanistic advantage of this modification stems from avoiding competing N-deprotonation, which presumably reduces the electrophilicity of the amide group under the classical conditions. Examples of this approach to date appear to have been limited to reactants with a EW substituent at the o-alkyl group[15,16]. 

Retrosynthetic path b in Scheme 3.1 corresponds to reversal of the electrophilic and nucleophilic components with respect to the Madelung synthesis and identifies o-acyl-iV-alkylanilines as potential indole precursors. The known examples require an aryl or EW group on the iV-alkyl substituent and these substituents are presumably required to facilitate deprotonation in the condensation. The preparation of these starting materials usually involves iV-alkyla-tion of an o-acylaniline. Table 3.3 gives some examples of this synthesis. 

Madelung synthesis of indolesl is initiated only by strong bases at elevated temperatures. Prior deprotonation of the amide group greatly reduces the electrophilicity of the carbonyl group, and the useful scope of this synthesis is therefore limited to molecules which can survive very drastic conditions (scheme 1)... 

Two of these reactions are, in the most general terms, examples of intramolecular aldol condensations. Path A, which includes the Madelung method and its variants, uses o-substituted anilides as starting materials. Path B reverses the electrophilic and nucleophilic components for C2—C3 bond formation. Among the classic indole syntheses corresponding to the first pattern is the Madelung synthesis, exemplified by the preparation of 2-methylindole from iV-acetyl-o-toluidine (Equation (16)) <550SC597>. 

Among other classic but useful indole syntheses are those of Bis-chler (1892) and Madelung (1912). In the Bischler synthesis, an aniline derivative is alkylated by an alpha-haloketone. Heating the product (9.81) effects the electrophilic attack of the carbonyl group on the benzene ring the loss of water from the product gives the indole structure (Scheme 9.38). 

The Saegusa indole synthesis involves the strong-base promoted cyclization of ort/ o-tolylisocyanides to indoles (Scheme 1) [1-5], Thus the Saegusa indolization resembles the Madelung indole synthesis. The reaction proceeds by a 5-endo-dig cyclization of 2 to form indole (equation 1). The isocyanide anion 2 was alkylated and subsequently cyclized to form 3-substituted indoles (equation 2). The quenching of 2 with epoxides yielded tryptophols (equation 3 and 4 and 5). Reaction of the ultimately formed N-lithioindole with electrophiles gave Af-substituted indoles (equation 4). 

---