Fischer indole synthesis thermal

Unsaturated hydrazones, unsaturated diazonium salts or hydrazones of 2,3,5-triketones can be used as suitable precursors for the formation of pyridazines in this type of cyclization reaction. As shown in Scheme 61, pyridazines are obtainable in a single step by thermal cyclization of the tricyanohydrazone (139), prepared from cyanoacetone phenylhydrazone and tetracyanoethylene (76CB1787). Similarly, in an attempted Fischer indole synthesis the hydrazone of the cyano compound (140) was transformed into a pyridazine (Scheme 61)... 

The Fischer indole synthesis can be regarded as the cyclization of an arylhydrazone 1 of an aldehyde or ketone by treatment with acid catalyst or effected thermally to form the indole nucleus 2. ... 

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

In a process related to the Fischer indole synthesis, arenesulfinamides 96 underwent thermal conversion into the corresponding indoles 97 via a [3.3] sigmatropic rearrangement followed by cydization and loss of HSOH <96BSF329>. 

A Neber route to substituted indoles 532, complementary to the Fischer indole synthesis, was recently developed (equation 235). Formation of azirine 531 from the oxime was smoothly induced, for example using MsCl/DBU or DIAD/BU3P or PhsP, and the intermediate was isolated. Thermal rearrangement of the azirine (40 to 170 °C, depending on the azirine structure) produced the indoles 532 directly in usually good yields (84-88% from the azirine). 

The thermal conversion of arylhydrazones in the presence of a protic acid or a Lewis acid to form an indole ring. See OweUen, R.J., Fitzgerald, J.A., Fitzgerald, B.M. et al.. The cyclization phase of the Fischer indole synthesis. The structure and significance of Pleininger s intermediate. Tetrahedron Lett. 18, 1741-1746, 1967 Kim, R.M., Manna, M., Hutchins, S.M. et al., Dendrimer-supported combinatorial chemistry, Proc. Natl. Acad. Sci. USA 93, 10012-10017, 1996 Brase, S., Gil, C., and Knepper, K., The recent impact of solid-phase synthesis on medicinally relevant... 

The Fischer indole synthesis has become the most popular method to prepare indole rings since its discovery in 1883 by Emil Fischer.In essence, the Fischer indole synthesis can be regarded as the cyclization of an arylhydrazone, prepared from an arylhydrazine, an aldehyde, or a ketone, by treatment with an acid catalyst or effected thermally to form the indole nucleus. The mechanism has been the subject of intensive investigations for over a century, and many intermediates have been isolated and characterized. By consensus from both theoretical and experimental evidence, the Fischer indole synthesis proceeds as shown below" ... 

Toward this end, a Fischer indole synthesis employing 4-carbethoxycyclo-hexanone (212) and phenyl hydrazine in warm acetic acid was followed by reduction of the resulting indole with lithium aluminum hydride to fomish hydroxymethyltetrahydrocarbazole 213. Alcohol activation with tosyl chloride and subsequent displacement of the tosylate with cyanide yielded nitrile 214. Oxidation with periodic add in methanol then formed ketone 215. Reduction of both the nitrile and carbonyl moieties was next achieved using lithium aluminum hydride in a mixture of THF and glyme at reflux to furnish aminoalcohol 216. A thermal dehydrative cyclization via heating this product in o-dichlorobenzene at reflux then led to 1,3-(iminoethano)carbazole 83. 

Several workers have described Fischer indolization without the use of acidic catalysts, the epitome of green chemistry. These thermal syntheses are shown in Table 2 [66-68]. The first practical account of noncatalytic Fischer indole synthesis appears to be that of Fitzpatrick and Riser (entries 1-3) [66]. Matsumoto and colleagues have effected indolizations with p-toluenesulfonic acid in the absence of solvent at 250 C to afford indoles 1-4 from the corresponding ketones and phenylhydrazine hydrochlorides (Scheme 5) [69]. In some cases, ttichloroacetic acid was employed. 

When the Fischer synthesis is applied to an unsymmetrical ketone, either one of two isomers or a mixture of them may be produced. (+)-3-MethylcycIopen-tanone gives a mixture of I- and 2-methylcyclopent[0]indoles, and the relative amounts of these formed under various conditions are analysed [3222]. Further work has recently been published on the Fischer indolization of -methoxy-phenyl- -phenylhydrazones of an unsymmetrical ketone (ethyl pyruvate). Cyclization in acid occurs mostly on to the more electron-rich benzene ring whereas under nonacidic (for example, thermal) conditions there is less regio-selectivity [3539]. 2-Methoxyphenylhydrazine sometimes behaves anomalously and does not yield the expected 7-methoxyindole, but when o-4-toluenesuIphonyl-or o-4-trifluoromethylsulphonyI-phenylhydrazine is used to prepare the hydra-zone, the main product is the 7-sulphonyloxyindole which may be hydrolysed to the 7-hydroxyindole with alkali [3629]. 

A practical application of the Fischer method is found in the synthesis of the anti-inflammatory dmg indomethacin (Scheme 9.42). Hydrazone 9.82 gives the expected indole product 9.83 on acid treatment. The COOH group is protected by conversion to the t-butyl ester 9.84 employing DCC as a dehydrating agent. Ester 9.84 is subjected to benzoylation with para-chlorobenzoyl chloride and base, and the t-butyl group is removed thermally in the final reaction to give indomethacin (9.85). 

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