Madelung reaction

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. ... 

Most syntheses of aza-indoles start from pyridines and parallel the standard indole syntheses discussed above. However, the Fischer reaction using pyridyl-hydrazones is much less consistent and useful than for arylhydrazones the Madelung reaction is also not as useful, however the Bartoli route" (20.16.1.9) and the Gassman approach" (20.16.1.12) can be used to effect. The most successful methods involve palladium-catalysed coupling of acetylenes with amino-halo-pyridines either as one-" or two-step " processes. The starting amino-halo-pyridines are generally available via directed metaUations. 

Cyclization of vicinal alkyl acylamines (139) induced by strong bases [the Madelung reaction and its modifications (68AHC27)] is a versatile method for preparing fused pyrroles (140) in the general representation in Scheme 31 the intermediate is depicted as a carbanion for simplicity, although N-deprotonated species are doubtless involved at some stage, as in Scheme 33. 

An efficient synthesis of iV-ethyl-l-hydroxy-7-methoxymitosane (115) was reported by Verboom and co-workers [39, 40]. This synthesis was based on a variation of the Madelung reaction in which the cyclization to an indole was facilated by an electron-withdrawing cyano group on the benzylic carbon (Scheme 15). The starting material, 2-amino-5-methoxy-4-methylbenzonitrile (110), was treated with 4-chlorobutyryl chloride to give amide 111, which was... 

Stevens and colleagues extended the base-promoted reverse-Madelung reaction to a vinylogous version (Scheme 3, equation 1) [22]. Among the many 2-acyl-3-indole esters (and carboxylic acids) that were prepared are 5-7. This clever tactic has been used by Opatz [23, 24] and Webb [25] as summarized in Table 2. Scheme 4 depicts the reaction pathway and includes some of Opatz s examples (8-10). 

Indole 90 was synthesized by a modified Madelung reaction from the amide 89 by treatment with potassium tcrt-butoxide. The presence of two strong electron-withdrawing groups (CN and CF3) in 89 facilitated both the deprotonation to the benzyl anion and its intramolecular cyclization under very mild conditions. Formation of 90 was completed in 10 min at room temperature in 81 % yield [39]. 

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. 

The principle that embodies this relationship can be stated as the products will be those in which the smaller ions will combine with oppositely charged ions of higher charge. In these cases, the Madelung constants may be different, so other factors may be involved. However, the principle correctly predicts reactions such as the following ... 

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). 

The Madelung synthesis of indoles (79 — 80) from A-acyl-o-toluidines originally necessitated heating with sodamide at 250°C however, the stronger bases n-butyllithium or LDA cause reaction at 20°C <81JOC4511 >. Milder conditions can also be employed if the methyl group is activated as in (81 — 82) (68JA7008). 

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). 

Figure 12. The Madelung sum of all die coulomb interactions of die electrolytes and their counterparts in base reduce to interactions between point charges as shown and die reaction center.

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