Fischer indole synthesis mechanism

Cyanohydrin-O-diethyl phosphates in indole chemistry 88YGK1165. Fischer indole synthesis, mechanism of 88KGS867. 

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 ... 

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. 

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

Fischer indole synthesis. 1. 54-69 anomalous products from, 64- 65 catalysts and conditions for. 54 - 55, 59-61 mechanism of, 54-55... 

You are about to see one of the great inventions of organic chemistry. It is a remarkable reaction, amazing in its mechanism, and it was discovered in 1883 by one of the greatest organic chemists of all, Emil Fischer. Fischer had earlier discovered phenylhydrazine (PhNHNH2) and, in its simplest form, the Fischer indole synthesis occurs when phenylhydrazine is heated in acidic solution with an aldehyde or ketone. 

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. 

In addition to its use in structural establishment of indoles, NMR has been widely applied to the study of (a) the protonation of indoles, (b) the stereochemistry of the side-chain substituents, and (c) the mechanism of the Fischer indole synthesis. 

The most prominent examples of this type of reaction are the Fischer Indole synthesis, the Beckmann rearrangement and the benzylamine rearrangement. For all three reactions rather complex mechanisms have been proposed. On comparing the structure- activity relationships for these transformations, it becomes clear that generalisations are difficult and that a complex interplay between pore shape and size, the acid strength and the polarity of the zeolite lattice seems to control the activity and selectivity for a given reaction. 

The hydrazine 140 rearranged when refluxed with HBr in acetic acid solution to furnish the two indole derivatives 141 and 142232 (equation 54). The formation of product 141 is in agreement with the mechanism of the Fischer indole synthesis vide infra). 

The mechanism of the Fischer indole synthesis is related to that of the benzidine rearrangement.91 This synthesis consists of the preparation of indole and substituted indoles by heating the phenylhydrazones or substituted phenylhydrazones of aldehydes, ketones, or oxo acids with reagents such as zinc chloride, or mineral acids that lead to elimination of ammonia, thus 92... 

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.)... 

A key observation as a result of these revised stereochemical assignments is that the stereochemistry of the Ban amino ketone (373) is now different from that of the natural series of compounds in which the C/E ring junction (A/ in 373) is cis. Stork s amino ketone (393) therefore has the correct stereochemistry, and the elaborate mechanism proposed to account for the total synthesis of natural aspidospermidine (249) (which originally involved isomerization at C-21) is unnecessary. What became important, however, was the identity of the product from a Fischer indole synthesis of 373. If Stork was correct and epimerization at C-21 is possible, then aspidospermidine should still be the product. If epimerization is not possible a new stereoisomer of aspidospermidine should result in which the C-21 proton and the C-20 ethyl group are trans. 

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" ... 

The Fischer indole synthesis has been the staple of assembling indoles for over a century. However, it does not work for ALL substrates. Propose a reasonable mechanism explaining why some Fischer indolizations... 

The mechanism is similar to the Fischer Indole Synthesis as outlined below. 

This reaction was first reported by Fischer and Jourdan in 1883. It is a synthesis of indole derivatives by the treatment of aryl hydrazones coupled from aromatic hydrazines and ketones or aldehydes with either a mineral or Lewis acid. Therefore, it is generally known as the Fischer indole synthesis. In addition, it is also referred to as Fischer cyclization, Fischer indole cyclization, Fischer indole reaction, Fischer indolization, Fischer reaction, and Fischer indole annulation. Although the mechanism has been extensively studied, the one formulated by Robinson and Robinson is now generally accepted. It involves the following steps (a) initial acid-catalyzed tautomerization of an aromatic hydrazone to an ene-hydrazine, b) a [3,3]-sigmatropic rearrangement of ene-hydrazine to a M-imine intermediate, (c) re-aromatization to aniline, d) intramolecular nucleophilic attack to form aminal, and (e) extrusion of an ammonia to afford the indole. 

The mechanism of the Fischer indole synthesis has been extensively studied [11-38], and the accepted mechanism is shown in Scheme 1. The so-caUed abnormal Fischer indoli-zation (Scheme 2) has been studied by Ishii and Muiakani and their coworkers [39-44], and the interrupted Fischer indolization (Scheme 3) has been evaluated theoretically by Houk, Garg, and colleagues [38],... 

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