Indole Madelung synthesis

Indole Ring Synthesis From Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John Wiley Sons, Ltd. 

A collection of Madelung indole syntheses using electron-withdrawing activation of the benzylic methylene group and other variations is summarized in Table 2 [38 3]. That extreme mildness is possible is shown by the cyclization in Entry 1, and Entry 4 features the synthesis of a new class of in vivo agonists. 

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.  

In 1912, Madelung reported that o-acetotoluidine 3 and o-benzotoluidine 5 provided the corresponding 2-methylindole 4 and 2-phenylindole 6 respectively when heated to 360-380 C with 2 molar equivalents of sodium ethoxide.  

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.  

Houlihan et al. have described the successful indolization of iV-acylated-o-alkylanilines by employing -BuLi/LDA as bases at lower temperature.  

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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 modification of the Madelung indole synthesis achieved by introduction of an electron withdrawing group (EWG) at the benzylic carbon atom of the N-acylated-o-alkylanilines has been quite successful. Orlemans et al. reported that indoles were isolated in decent yields when the amides were treated with t-BuOK in THF for a period of 10 minutes at room temperature. ... 

The Madelung indole synthesis has been employed in the preparation of some complex indole systems. Uhle et al. reported the conversion of N-formyl-5,6,7,8-tetrahydronaphthylamine 28 into 1,3,4,5-tetrahydrobenz[c,ti]indole 29 with t-BuOK in 11% yield in regard to synthesis of ergot alkaloids. ... 

The ring closure (83 — 84) involves an intramolecular Wittig reaction (81CC14). Another variation on the Madelung indole synthesis is provided by the cyclization of o-isocyanobenzenes (85 — 86) (77JA3532). 

Smith-modified Madelung Indole synthesis (Smith indoie synthesis) ... 

Madelung indole synthesis The intramolecular cyclization of N-acylated-ortho-alkylanilines to afford 2,3-disubstituted indoles. 270... 

Related reactions Fischer indole synthesis, Larock indole synthesis, Madelung indole synthesis, Nenitzescu indole synthesis ... 

Houlihan, W. J., Parrino, V. A., Uike, Y. Lithiation of N-(2-alkylphenyl)alkanamides and related compounds. A modified Madelung indole synthesis. J. Org. Chem. 1981,46, 4511-4515. 

MADELUNG Indole Synthesis Indole synthesis by cyclization of N-acyl-o-toluidines, (see 1st edition). 

NH Deprotonations. During a modified Madelung indole synthesis, the convergent high-yielding condensation of the two main fragments of (—)-penitrem D, Ai-silylation (1.1 equiv BuLi) and lateral metalation (j-BuLi) of a complex o-toluidine substrate followed by condensation with a lactone fragment is carried out (eq 69). ... 

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