Fischer arylhydrazones

Retrosynthesis a in Scheme 7,1 corresponds to the Fischer indole synthesis which is the most widely used of all indole syntheses. The Fischer cyclization converts arylhydrazones of aldehydes or ketones into indoles by a process which involves orf/io-substitution via a sigmatropic rearrangement. The rearrangement generates an imine of an o-aminobenzyl ketone which cyclizes and aromatizes by loss of ammonia. 

The issue of regioselectivity arises with arylhydrazones of unsymmetrical ketones which can form two different enehydrazine intermediates. Under the conditions used most commonly for Fischer cyclizations, e g. ethanolic HCI, the major product is usually the one arising from the more highly substituted enehydrazine. Thus methyl ketones usually give 2-methy indoles and cycliz-ation occurs in a branched chain in preference to a straight chain. This regioselectivity is attributed to the greater stability of the more substituted enhydrazine and its dominance of the reaction path. 

The oxygen analogue of the Fischer cyclization requires the formation of 0-vinyl derivatives of iV-arylhydroxylarnines. These are readily converted to indoles but are less readily accessible than the arylhydrazones used for the Fischer cyclization. 

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. ... 

The first indolization of an arylhydrazone was reported in 1983 by Fischer and Jourdan" by treatment of pyruvic acid 1-methylphenylhydrazone 3 with alcoholic hydrogen chloride. However, it was not until the following year that Fischer and Hess identified the product from this reaction as 1-methyl indole-2-carboxylic acid 4. 

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 addition to /3-diketones, /3-ketoacids and /3-ketoesters, cyanoacetic ester and related compounds are suitable starting materials. The arylhydrazones 4 thus obtained are of great importance as starting materials for the Fischer indole synthesis, as well as for the preparation of other iV-heterocycles. ... 

When arylhydrazones of aldehydes or ketones are treated with a catalyst, elimination of ammonia takes place and an indole is formed, in the Fischer indole synthesis,Zinc chloride is the catalyst most frequently employed, but dozens of others, including other metal halides, proton and Lewis acids, and certain transition metals have also been used. Microwave irradiation has been used to facilitate this reaction. Aniline derivatives react with a-diazoketones, in the presence of a... 

A classical method for synthesizing indoles is by the Fischer indolization, which involves the cyclization of arylhydrazones in the presence of strong acids. Lipinska... 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

Construction of the indole ring via Fischer synthesis. Starting from a variety of 3,4-dihydro-lH-benzo[l ]azepine-2,5-diones 40 and arylhydrazines Fischer syntheses of indolo benzazepinones 41 have been reported (Scheme 8 (1999JMC2909)). Usually, the reaction comprises a two-step one-pot procedure with the formation of intermediate arylhydrazones in warm acetic acid followed... 

The synthesis of cyclic ethers 137 was achieved by a Fischer indole synthesis starting from cyclic keto arylhydrazones generated in situ from 4-(hydroxy-methylene)-3,4-dihydrobenzo[ 7]oxepin-5(2H)-one 136 and the corresponding diazonium salt (Equation (20), 1993JHC1481). 

The Fischer method (497) of indole synthesis by the indolization of an arylhydrazone by treatment with an acid catalyst was applied to the synthesis of tetrahydrocarba-zoles by Borsche (498). 

Fischer indole synthesis Cyclization of arylhydrazones by heating with an acid or Lewis acid catalyst yields an indole system. The most commonly used catalyst is ZnCl2- The disadvantage of this reaction is that unsymmetrical ketones give mixtures of indoles if R also has an a-methylene group. 

Ilac Fischer indole synthesis from /V-arylhydrazones 3.06.3.4.2... 

The Fischer indole synthesis is the conversion of an Af-arylhydrazone to an indole with elimination of ammonia (equation 88). This method is of very broad scope, and is able to accomodate a wide variety of functionalized and unfunctionalized 2- and 3-side chains as well as substituents in the carbocyclic ring (B-70MI30605,72HQ25-D232). Ironically, the parent 2,3-unsubstituted indoles are difficult to obtain via the Fischer method. Indole itself was not successfully made by the Fischer method until 1976, and then only using a high temperature (290-300 °C) procedure (76JOC1877). 

Processes include the Fischer indole synthesis from arylhydrazones and related sigmatropic syntheses, reductive evclizations of nitni compounds, the Madelung synthesis from anilides and related base-cululyxed condensations. and transition-metal catalyzed cyclizations,... 

The Fischer Indole Synthesis and Related Sigmatropic Syntheses. In the Fischer indole synthesis (26) an N-arylhydrazone is cyclized, usually under acidic conditions, to an indole. The key step is a [3,3]sigmatropic rearrangement of an enehydrazone tautomer of the hydrazone. 

The use of arylhydrazones for the synthesis of indoles has been widely discussed in the literature [1,2, 169], One of the most useable methods is the Fischer reaction [169, 170, 171], modified by Arbuzov [172],... 

Arylhydrazones containing diethoxyphosphoryl group cyclize to 2-phosphorylindoles 167 according to the scheme of the Fischer reaction [175] ... 

The Fischer indole synthesis. The Fischer acid-catalyzed conversion of an 7V-arylhydrazone 42 into an indole is one of the most powerful and versatile methods for the preparation of indoles . The mechanism involves a [3,3] sigmatropic Claisen-type rearrangement of a protonated enehydrazine tautomer 43 to give intermediate 44, which spontaneously cyclizes by loss of ammonia, probably via indoline 45, to an indole 46 (Scheme 27). For unsymmetrical ketones, two isomeric indoles are possible and the general result is that the indole derived from the more stable (usually the more highly substituted) enehydrazine is formed. 

Factors Controlling the Regioselectivity in the Fischer Indole Synthesis The Fischer indole reaction has been extensively used for the synthesis of indole derivatives [77]. A problem is that two isomeric indoles are possible when the reaction is applied to arylhydrazones from dissymmetric methylene ketones, see Scheme 10. 

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... 

Pyridazinones were obtained from an attempted Fischer indolization of a cyclopentanone phenylhydrazone [85CI(L)697], from hydrazones of unsaturated 1,4-keto esters (87H2101) or from 3-arylhydrazones of 4-(4-methoxyphenyOglutaconic anhydride in the presence of seconday amines [83IJC(B)512]. Pyridazines 6 can be synthesized from 2-phenylhydrazones of 1,2,3-tricarbonyl compounds and phosphacumulenylides (80TL2939 85CB1709). 

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