Solid-Phase Madelung Indole Synthesis

The reaction proved to be quite flexible both electron-rich and electron-poor substituted benzanilides worked well, as did heteroaroyl anilides, saturated heterocycle anilides, and alkyl anihdes. The presence of competitive acidic a-hydrogens or of a,P-unsaturated acyl residues did not lead to good results. For greater diversity, the cyano group of the original aniline could be efficiently replaced by a tert-butyl ester or a dimethylamide. Cleavage from the resin was performed with GH2Gl2/TFA/triethylsilane (94 5 1, v/v/v). The product (603) was then dried in vacuo at 40 °C. 

Other approaches to indoles based on transition metal-mediated couplings have been outlined in Sections 4.2.2 and 4.2.4. Nicolaou et al. recently described a novel solid-phase synthesis of substituted indolines and indoles [414]. 

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Scheme 5 Wacker Solid-Phase Madelung Indole Synthesis...

Hughes developed a polymer-bound phosphonium salt support for a solid phase Wittig-Madelung indole synthesis (Scheme 8) [21]. The method uses a commercially available polymer-bound triphenylphosphine 22. 

Combinatorial chemistry has played an increasing role in drug discovery. Wacker et al. extended the Madelung indole process successfully to solid phase library synthesis for the preparation of 2,3-disubstituted indoles. A number of examples follow in the table. 

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. 

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