Madelung synthesis preparation

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 most successful method for preparing azaindoles has been the Madelung synthesis, which involves a base-catalyzed cyclization of o-acylaminotoluenes or picolines. Eighteen azaindoles have been prepared by various modifications of the Madelung ring closure. These are summarized in Table I. 

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>. 

Pindur and Eitel prepared several 2-vinylindoles via a Wittig-Madelung synthesis (Scheme 3, equation 1), work that included the first synthesis of the parent 2-vinylindole [10]. Imaniski and colleagues prepared a series of 2-trifluoromethylindoles via a Wittig-Madelung... 

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 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. ... 

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. 

The 2,2 -bisindole (1384), required for the synthesis of staurosporinone (293) and the protected aglycon 1381, was prepared by a double Madelung cyclization as reported by Bergman. For the synthesis of the diazolactams 1382 and 1383, the glycine esters 1385 and 1386 were transformed to the lactams 1389 and 1390 by DCC/DMAP-promoted coupling with monoethyl malonate, followed by Dieckmann cyclization. The lactams 1389 and 1390 were heated in wet acetonitrile, and then treated with mesyl azide (MsNs) and triethylamine, to afford the diazolactams 1382 and 1383. This one-pot process involves decarboethoxylation and a diazo transfer reaction (Scheme 5.234). 

Somewhat related to the Madelung and Wender indole syntheses is the method developed by Smith and Visnick, which features the dilithio species from ortho-sXkyl-N-in-methylsilyl anilines reacting with carboxylic acid esters to give 2-substitnted and 2,3-disubstituted indoles [1, 2], The value of this indole synthesis is seen by its numerous applications by Smith and coworkers in the synthesis of indole alkaloids [3-12], The basic reaction and some examples are shown in Scheme 1. The requisite silylated anilines were prepared by lithiation (n-bntyllithinm, -78 °C) of the aniline followed by quenching with trimethylsilyl chloride. For the synthesis of 2,3-disubstituted indoles an inverse quench is preferred (equation 3). To lithiate ort/to-ethyl-A -methylsilyl aniline, n-butyllithium-tetramethylethylene-diamine (TMEDA) was required. Indole 1 is an intermediate in the synthesis of (H-)-cinchonamine. 

Recent advances in the synthesis and properties of 4-, 5-, 6-, and 7-azaindoles have been published (13T4767). Rashinkar prepared a series of azaindoles via a modified Madelung indole synthesis. Aminopyridine 261 was treated with acid 262 in the presence of a coupling reagent (BOP-Cl) and base subsequent cyclization furnished azaindole 263 in moderate to good yields (13TL6858). 

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