Fischer indole synthesis methods

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 ... 

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

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. 

A solid phase library synthesis method based on the Fischer indole synthesis was developed (Scheme A resin-capture-release method... 

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). 

The Fischer indole synthesis has been extended to the synthesis of benzofurans as shown in a recent synthesis of 4,5, 8-trimethylpsoralen (Scheme 60) (79JOC2176). The availability of methods for the synthesis of the precursor O-aryloximes limits its application. 

Dimethylindole was obtained from phenylhydrazine and butan-2-one, by a one-pot reaction in water (Scheme 9.10, Eq. 1). This is the first example of water as the reaction medium for Fischer indole synthesis, and significantly neither a preformed hydrazone nor addition of acid was required. Also, the decarboxylation of indole-2-carboxylic acid to afford indole is not trivial by traditional methods. However, in water... 

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. 

The Fischer indole synthesis is a versatile method for preparing 2,3-substituted indoles. Indoles itself, in small concentrations, has a floral odour while many of 2,3-substituted indoles are biologically active and also find applications as pharmaceuticals and plant growth regulators. 

The synthesis of azaindoles by the Fischer indole synthesis has been tried more often than by any other method. It has given varied results, with over thirty successful ring closures of pyridyl- or quinolyl-hydrazones reported. Most of these have led to carboline deriva-... 

Fischer indole synthesis. The synthesis of a 2-substituted indole by the method of Fischer " can be interpreted as shown in the formulation. An Organic Syntheses preparation of 2-phenylindole specified heating acetone phenylhydrazone with five times its weight of zinc chloride al 170° and adding 4 parts of sand to prevent solidification on cooling (yield of 2-phenyllndole 72-HO%). Chapman el /. studied various cyclizing agents (coped, hydrochloric acid, dry HCI, BFn. polyphosphoric... 

The PLS method is also the appropriate tool for determining which properties of the reaction system have an influence on the experimental results. An extensive study of the Fischer indole synthesis was given as an example. For analysis of this type of problem, an experimental design which affords a uniform spread in the principal properties should be used. 

Serotonin has been synthesised by several routes the method shown relies on a Fischer indole synthesis, the requisite aryl-hydrazone being constructed by a process known as the Japp-Klingemann reaction in which the enol of a 1,3-dicarbonyl compound is reacted with an aryl-diazonium salt, with subsequent cleavage of the 1,3-dicarbonyl unit. 

The Bischler-Napieralski (BN) method has demonstrated great utility for fully aromatic P-carboline rings. Substitution on carbocyclic ring A of the p-carboline system requires suitably substituted tryptamine which can be prepared via the Fischer indole synthesis or one of several methods for synthesis of indole rings (28, 128). 

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... 

Indoles are a special case as there is one pre-eminent method the Fischer indole synthesis. The phenylhydrazone (38) of a ketone is treated with acid (or-Lewis acid —ZnCl2 is often used). Tautomerisation to (39) is followed by a... 

Phenylindole is prepared from the reaction of acetophenone and phenylhydrazine, a method known as the Fischer indole synthesis. Propose a mechanism for this reaction. Hint The reactive species is the enamine tautomer of the phenylhydrazone.)... 

Fischer indole synthesis. This reaction can be carried out by reaction of a ketone (1 equiv.) and an arylhydrazine hydrochloride (1 equiv.) in refluxing pyridine (1-18 hours). Pyridinium chloride (1 equiv.) is formed and acts as catalyst for the cyclization to indoles. No prior formation of a hydrazone is required. In several instances, higher yields are obtained by this method than by use of other catalysts. ... 

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