Toluidines, indoles from

Baeyer and Caro obtained indole by passing the vapour of ethylaniline through a red-hot tube, and also synthesised it from diethyl o-toluidine. Indole was prepared from isatic acid (o-NH2 C6H4 CO C02H) by Baeyer s pupil W. Suida and isatin synthesised from o-nitrobenzoic acid by Claisen and J. ShadwelL ... 

One type of o-aminobenzyl anion synthon is a mixed Cu/Zn reagent which can be prepared from o-toluidines by / i.s-trimethylsilylation on nitrogen, benzylic bromination and reaction with Zn and CuCN[l]. Reaction of these reagents with acyl halides gives 2-substituted indoles. 

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). 

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>. 

Highly nucleophilic aromatic compounds are capable of arylating acyl-pyridinium salts. The first example of this striking reaction was described by Koenigs and Ruppelt s ho observed the formation of 4-(/>-dimethyl-aminophenyl) pyridine from pyridine, benzoyl chloride and dimethyl-aniline in the presence of copper. Benzaldehyde is also formed s, 736 and the copper is not necessaryThe dihydropyridine (105) is probably an intermediate. Other examples of the reaction are known s, 493 but attempts to isolate the intermediates have failed , though that from dimethyl-m-toluidine may have been obtained. In contrast, the dihydropyridines (106) were isolated when indole was the nucleophile. Skatole reacted similarly, at the 2-position of the indole nucleus, giving the fully aromatic 3-methyl-2-(4 -pyridyl)indole. These reactions failed with 2- and 4-picoline . Similar reactions occur between acylpyridinium salts and pyrroles (p. 71). 

The indole nucleus is present in various bioactive molecules and many selective protocols for its construction have been developed. Classical methods for the indole synthesis include the Fischer indole synthesis, the Batcho-Leimgruber synthesis from o-nitrotoluenes and dimethylformamide acetals, the Gassman synthesis from N-haloanilines, the reductive cyclization of o-nitrobenzyl ketones, and the Madelung cyclization of A/ -acyl-o-toluidines [42,43]. 

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