Fischer indolization

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 ... 

Benzilic acid rearrangement Benzoin reaction (condensation) Blanc chloromethylation reaction Bouveault-Blanc reduction Bucherer hydantoin synthesis Bucherer reaction Cannizzaro reaction Claisen aldoi condensation Claisen condensation Claisen-Schmidt reaction. Clemmensen reduction Darzens glycidic ester condensation Diazoamino-aminoazo rearrangement Dieckmann reaction Diels-Alder reaction Doebner reaction Erlenmeyer azlactone synthesis Fischer indole synthesis Fischer-Speior esterification Friedel-Crafts 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. 

Phosphorus trichloride in benzene is reported to effect mild and fast cydization. It has been used for synthesis of 2,3-dialkyl- and 2,3-diaryl-indoles[8-ll]. Table 7.2 presents some typical Fischer indolization reactions using both the traditional and more recently developed reaction conditions. 

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... 

Fischer indole cyclizations incorporating functionalized substituents... 

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. 

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 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 number of reaction pathways have been proposed for the Fischer indolization reaction. The mechanism proposed by Robinson and Robinson in 1918, which was extended by Allen and Wilson in 1943 and interpreted in light of modem electronic theory by Carlin and Fischer in 1948 is now generally accepted. The mechanism consists of three stages (I) hydrazone-ene-hydrazine equilibrium (II) formation of the new C-C bond via a [3,3]-sigmatropic rearrangement (III) generation of the indole nucleus by loss of... 

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...

Many aryhydrazones provide two or more isomers when subjected to the conditions of the Fischer indole cyclization. The product ratio and the direction of indolization can also be affected by different reaction conditions (i.e. catalysts and solvents), which is attributed, at least in part, to the relative stabilities of the two possible tautomeric ene-hydrazine intermediates. Generally, strongly acidic conditions favor formation of the least substituted ene-hydrazine, while cyclization carried out in weak acids favors the most substituted ene-hydrazine. Eaton s acid (10% P2O5 in MeSOsH) has been demonstrated to be an effective catalyst for the preparation of 3-unsubstituted indoles from methyl ketones under strongly acidic conditions. Many comprehensive reviews on this topic have appeared. ... 

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