The Fischer indole synthesis

Indoles are an important class of fine chemicals derivatives find application as fragrance chemicals. The indole nucleus is present in many biologically active molecules including plant-growth regulators, proteins and pharmaceuticals. The selective synthesis of indole derivatives constitutes an important area of drug research. The well-known Fischer indole synthesis provides a versatile method for synthesizing substituted indoles from the arylhydrazones of aldehydes or ketones 

Although in favorable circumstances the reaction may be effected thermally, it is usually conducted as an acid-catalyzed reaction. Both Brpnsted and Lewis acids are effective. The principal function of the catalyst is to accelerate the formation of the enehydrazine from the arylhydrazone [5,6]. It is not usually necessary to isolate the latter the reaction can be conducted as a one-pot procedure starting from ketone or aldehyde and arylhydrazine. Catalysts employed include mineral acids (hydrochloric, sulfuric, polyphosphoric), organic acids such as acetic acid, and metal-halide Lewis acids. Among the most generally reported are ZnCl2 and alcoholic hydrogen chloride. 

The homogeneous Brpnsted and Lewis acids employed traditionally require neutralization during product work-up and thus generate salt and/or metal-containing 

In a series of papers, Suvorov et al. investigated heterogeneous catalysis of the cyclization of isolated aldehyde and ketone phenylhydrazones. y-Alumina was typically employed as catalyst in the vapor phase reaction at atmospheric pressure and at temperatures around 300 °C. A maximum yield of 60% was obtained from acetaldehyde phenylhydrazone as a result of thermal decomposition of the hydrazone [7] and the formation of benzene and aniline as by-products [8]. Kinetic studies indicated that the rate-determining step was desorption of product from the surface [9]. 

The effect of substituent groups was also studied. In a series of N-substituted hydrazones, PhNRN CMeEt, cyclization proceeded with increasing difficulty in the series R = H, Me, Et, Ph this was ascribed to the effect of increasing steric hindrance [12]. From acetaldehyde phenylhydrazones with methoxy substituents on the aromatic ring, yields were poor, which was attributed to decomposition of the substrate to non-volatile products on the alumina catalyst surface [13]. In contrast, with an acidic ion-exchange resin as catalyst, higher yields were obtained with the 4-methoxy derivative than with the 4-nitro this was interpreted as the effect of methoxy in facilitating adsorption on the resin [14]. 

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An important general method of preparing indoles, known as the Fischer Indole synthesis, consists in heating the phenylhydrazone of an aldehyde, ketone or keto-acld in the presence of a catalyst such as zinc chloride, hydrochloric acid or glacial acetic acid. Thus acrtophenone phenylhydrazone (I) gives 2-phenyllndole (I V). The synthesis involves an intramolecular condensation with the elimination of ammonia. The following is a plausible mechanism of the reaction ... 

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. 

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

The Fischer Indole Synthesis and Related Sigmatropic Syntheses. In the Fischer indole synthesis (26) an Ai-aryUiydra2one is cyclized, usually under acidic conditions, to an indole. The key step is a [3,3] sigmatropic rearrangement of an enehydra2one tautomer of the hydra2one. 

The Piloty-Robinson pyrrole synthesis (74JOC2575,18JCS639) may be viewed as a monocyclic equivalent of the Fischer indole synthesis. The conversion of ketazines into pyrroles under strongly acidic conditions apparently proceeds through a [3,3] sigmatropic rearrange-... 

Formation of a 1,2-disubstituted hydrazine by acid hydrolysis of an appropriately substituted pyrazolidine has been noted (67HC(22)l), but the most interesting ring fission of pyrazolidines involves the N(l)—N(2) bond of 1-phenylpyrazolidines (421). If, instead of phenylhydrazone, compound (421) is used in the Fischer indole synthesis, N- aminopropylin-doles are formed (73T4045). Scheme 39 shows the reaction with cyclohexanone. 

Intramolecular cyclization in perfluoroaromanc systems proves useful for the synthesis of heterocyclic compounds [72] For example, the Fischer indole synthesis, which normally requires the presence of an ortho proton, occurs satisfactonly with an ortho fluonne in theperfluoronaphthalene senes [73] (equation 37)... 

Robinson, B. The Fischer Indole Synthesis, Wiley-Interscience, New York, 1982. 

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. ... 

Over 100 years after the initial discovery, the Fischer indole synthesis remains the most commonly employed method for the preparation of indoles. ... 

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. 

Table 3.4.1. Commonly used catalysts for the Fischer indole synthesis...

In order to allow further transformation to an indole, the carbonyl compound 8 must contain an a-methylene group. The hydrazone 1 needs not to be isolated. An equimolar mixture of arylhydrazine 7 and aldehyde or ketone 8 may be treated directly under the reaction conditions for the Fischer indole synthesis. ... 

The Fischer indole synthesis is of wide scope, and can be used for the preparation of substituted indoles and related systems. For example reaction of the phenylhydrazone 9, derived from cyclohexanone, yields the tetrahydrocar-bazole 10 ... 

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. ... 

A microwave-assisted version of the Fischer indole synthesis was described by reaction of the hydrazone 179 [119]. The reaction was carried out on Mont-morillonite KIO doped with ZnCl2 giving reasonable yields of compound... 

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... 

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 somewhat more complex example of the Fischer indole synthesis is provided by the tranquilizer, milipertine (8). It can be prepared by reaction of... 

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

Interestingly, the Fischer indole synthesis does not easily proceed from acetaldehyde to afford indole. Usually, indole-2-carboxylic acid is prepared from phenylhydrazine with a pyruvate ester followed by hydrolysis. Traditional methods for decarboxylation of indole-2-carboxylic acid to form indole are not environmentally benign. They include pyrolysis or heating with copper-bronze powder, copper(I) chloride, copper chromite, copper acetate or copper(II) oxide, in for example, heat-transfer oils, glycerol, quinoline or 2-benzylpyridine. Decomposition of the product during lengthy thermolysis or purification affects the yields. 

Chemical Reactions. The Mechanism of the Fischer Indole Synthesis. J. Amer. chem. Soc. 65, 611 (1943). 

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