Indoles Madelung synthesis

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 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. 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). 

The indole formation from o-tolylisocyanide 23, which is brought about by metallation with lithium dialkylamides, is related to the Madelung synthesis. The lithium compound 24 can undergo cyclization to form indole (via iV-lithioindole) or, after alkylation and renewed metallation, to produce 2-substituted indoles ... 

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>. 

Wacker and Kasireddy described a solid-phase synthesis of 2,3-disubstituted indoles (Scheme 5) [37] via the modified Madelung synthesis reported by Reinhoudt [34, 35]. The basic approach is shown in equation 1, and several synthesized indoles are posted. 

Related to the principle of the Madelung synthesis is the indole formation starting from (o-tolyl)isocyanide (71). The isocyanide 71 can be metalated with Li-dialkylamides at the 0-CH3 group, and the resulting Li compound 72 may either undergo cyclization to indole (via N-lithioindole 74) or - after alkylation to 73 and renewed benzylic metalation and cyclization - produce 3-substituted indoles 75 [164] ... 

Madelung synthesis (indole) 137 Marckwald cleavage, of furans 79 Marckwald synthesis (imidazole) 224 Meth-Cohn synthesis (quinoline) 402 Meyer s oxazoline method 183 Morin reaction 456 Mukaiyama reaction 380 Mukaiyama reagents 53, 380... 

The classical conditions for the Madelung indole synthesis are illustrated by the Organic Syntheses preparation of 2-methylindole which involves heating o-methylacetanilide with sodium amide at 250 C[1]. 

The intramolecular cyclization of A -acylated-o-alkylanilines in the presence of a strong base at elevated temperatures is known as the Madelung indole synthesis. ... 

The mechanism of the Madelung indole synthesis has not been fully established. An intramolecular Claisen type condensation is presumably involved in the process. ... 

The most common conditions employed in the Madelung process are sodium/potassium alkoxide or sodium amide at elevated temperature (200-400 C). The Madelung reaction could be effected at lower temperature when -BuLi or LDA are employed as bases/ The useful scope of the synthesis is, therefore, limited to molecules which can survive strongly basic conditions. The process has been successfully applied to indoles bearing alkyl substituents. ... 

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