Madelung synthesis

The most successful method for preparing azaindoles has been the Madelung synthesis, which involves a base-catalyzed cyclization of o-acylaminotoluenes or picolines. Eighteen azaindoles have been prepared by various modifications of the Madelung ring closure. These are summarized in Table I. 

Koenigs and Fulde were the first to synthesize an azaindole directly by heating 3-acetamido-4-picoline (5, R = Me) with sodium 

15a Sterling Drug Inc., Netherlands Patent 6,414,916 (1965) Chem. Abstr. 64, 8152 (1966). 

Similarly, Clemo and Swan synthesized 7-azaindole (2) and its 2-methyl and 2-ethyl derivatives in low yields (3, 17, and 12 %. respectively). They failed to improve the yield by use of potassium 

Clayton and Kenyon prepared 5-methyl, 2,5-dimethyl-, and 2-phenyl-5-methyl-4-azaindole in 12,55, and 67 % yields, respectively, by treatment of the corresponding formyl, acetyl, and benzoyl derivatives of 3-amino-2,6-dimethylpyridine with sodium ethoxide at 310° for 15 minutes. The phenyl compound was prepared also by Protiva et al in 1 % yield. 

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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. 

The Madelung Synthesis and Related Base-Catalyzed Condensations. The Madelung cyclization involves an intramolecular condensation of an o-aLkylanilide. A classic example of the Madelung synthesis is the high temperature condensation of o-methylacetanihde [120-66-1] to 2-methylindole [95-20-5] by sodium amide. 

The Madelung synthesis of indoles (79 — 80) from A-acyl-o-toluidines originally necessitated heating with sodamide at 250°C however, the stronger bases n-butyllithium or LDA cause reaction at 20°C <81JOC4511 >. Milder conditions can also be employed if the methyl group is activated as in (81 — 82) (68JA7008). 

Processes include the Fischer indole synthesis from arylhydrazones and related sigmatropic syntheses, reductive evclizations of nitni compounds, the Madelung synthesis from anilides and related base-cululyxed condensations. and transition-metal catalyzed cyclizations,... 

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)... 

Madelung synthesis. Formation of indole derivatives by intramolecular cyclization of an N-(2-alkylphenyl)alkanamide by a strong base at high temperature. 

Treatment of an imidate which is placed ortho to a reactive methylene group with sodium hydroxide-DMSO results in the formation of a new pyrrole ring. Good to xcelient yields of 4-nitroindoles are obtained when 3-nitro-2-methyl-anilines (or acetanilides) are treated with diethyl oxalate in the presence of a strong base (cf. Madelung synthesis of indoles, p. 68). 

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