Indoles from o-alkylanilides-the Madelung synthesis

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]. 

These conditions are so harsh that they are applicable only to indoles with the most inert substituents. Cyclization can be achieved at much lower temperatures by using alkyllithium reagents as the base. For example, treatment of o-methylpivalanilide with 3 eq. of n-butyllithium at 25 C gives 2-terr-butylindole in 87% yield[2]. These conditions can be used to make 

2-arylindoles from benzanilides and have also been applied to the synthesis of azaindoles[3]. The reaction is presumed to proceed through a dilithiated intermediate which eliminates Li20[4], Table 3.1 gives some examples. 

A variation of the Madelung cyclization involves installing a functional group at the o-methyl group which can facilitate cyclization. For example, a triphenylphosphonio substituent converts the reaction into an intramolecular Wittig condensation. The required phosphonium salts can be prepared by starting with o-nitrobenzyl chloride or bromide[9]. The method has been applied to preparation of 2-alkyl and 2-arylindoles as well as to several 2-alkenylindoles. Tabic 3.2 provides examples. 

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