Madelung cyclization

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. 

Maddrell s salt Madelung cyclization Madopa Maduramicin... 

The Madelung Synthesis and Related Base-Catalyzed Condensations. The Madelung cyclization involves an intramolecular condensation of an o-aLkylanilide. A classic example of the Madelung synthesis is the high temperature condensation of o-methylacetanihde [120-66-1] to 2-methylindole [95-20-5] by sodium amide. 

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). 

In spite of these reported successes, the Madelung cyclization offers the following disadvantages (i) the drastic conditions necessary limit its application to the synthesis of unsubstituted or alkyl- and aryl-substituted azaindoles (ii) the reaction is often, if not always, intractable and Hi) yields are erratic, often unreproducible, and subject to such variables as stirring and heating efficiency, purity of starting materials, quality (or manufacturer ) of reagents, and operator. 

The harsh reaction conditions that are required reflect the low acidity of the methyl substituent and the fact that imder the reaction conditions the amide is presumably deprotonated and therefore hardly electrophilic. The Madelung cyclization can be done under much milder conditions by using two equivalents or more of an alkyllithium as the base (Equation (17)) <8iJOC45ll>. 

Bartoli and colleagues employed orf/to-trimethylsilyl-methyl anilides to effect a Madelung cyclization in an intramolecular Peterson olefination, as shown in Scheme 4 [35, 36]. Whereas a normal Madelung product is obtained in equation 1, a reverse Madelung compound is the result... 

One of the lesser known Nenitzescu name reactions is the cyclization of A-acetylphenylglycine-ort/t( -carbox-ylic acid 11 to A,0-diacetylindoxyl 12 (Scheme 5, equation 1) [26, 27]. While this precise reaction has a long history [28], it was Nenitzescu and colleagues who greatly improved the preparation of this important indole. As yon can see, the reaction involves an acid-promoted reverse-Madelung cyclization. Some examples of this... 

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]. 

---