Fischer-Indole synthesis

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 synthesis is often carried out by subjecting an equimolar mixture of the aryl hydrazine and aldehyde or ketone directly to the indolization conditions without isolation 

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. 

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 

Robinson, B. The Fisher Indole Synthesis, John Wiley Sons, New York, NY, 1982. 

Armengol, M. Femandez-Fomer, D. Tetrahedron 2001, 57, 1041. 

Fischer Indole Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 100—103. (Review). 

Often known as simply Fischer esterification , protic acid-catalyzed esterification of acid and alcohol. 

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- 

Early attempts to cyclize 2-quinolylhydrazones of acetone, acetaldehyde, acetophenone, and pyruvic acid, and a number of 2-pyridylhydrazones, under a variety of conditions failed. Later, however, Robinson and Robinson found that heating 2-methyl-3-hydrazinoquinoline in cyclohexanone gave only a product of uncertain structure described as a dioxide of the hydrazone, but in the presence 

Yakhontov, E. V. Pronina, and M. V. Rubtsov, DoM. Akad. Nauk SSSR 169, 361 (1966) Proc. Acad. Sci. USSR, Chem. Sect. English Transl.) 169, 705 (1966). 

48 Deutsche Gold- und Silver-Scheideanstalt vorm. Roessler, British Patent 259,982 (1925) Chem. Zentr. 991, 2311 (1928). Curiously, this patent does not appear to have been abstracted by Chem. Abstr. However, all the compounds, except the azaindoles, did appear in French Patent 641,422 (1926) Chem. Abstr. 23, 1139 (1929). 

Rath synthesized 3-hydrazinopyridine and prepared its propionaldehyde and pyruvic acid hydrazones with the intention of using them to make pyrindoles (azaindoles). Although he indicated the work was to be described in a subsequent publication, no mention of it could be found. 

The most useful route to indoles is the Fischer indole synthesis, in which an aromatic phenylhydrazone is heated in acid. The phenylhydrazone is the condensation product from a phenylhydrazine and an aldehyde or ketone. Ring closure involves a cyclic rearrangement process. 

The hydrazine behaves as an amine towards a carbonyl compound and forms the imine-like product, a hydrazone. The cyclic rearrangement involves the 

Unfortunately, the reaction fails with acetaldehyde and cannot, therefore, be used to synthesize indole 

The total synthesis of (+)-deethylibophyllidine was accomplished by J. Bonjoch and co-workers, who applied a regioselective Fischer indole synthesis as one of the key steps to obtain octahydropyrrolo[3,2-c]carbazoles. The indole formation was followed by a tandem Pummerer rearrangement-thionium ion cyclization to generate the quaternary spiro stereocenter. 

During the total synthesis of (+)-aspidospermidine by J. Aube et al., the final steps involved an efficient Fischer indolization of a complex tricyclic ketone. This ketone was unsymmetrical and the indole formation occurred regioselectively at the most substituted a-carbon in a weakly acidic medium (glacial AcOH). 

The unusual 6-azabicyclo[3.2.1]oct-3-ene core of the alkaloid (+)-peduncularine was assembled using the [3+2] annulation of an allylic silane with chlorosulfonyl isocyanate by K.A. Woerpel and co-workers. In the endgame of the total synthesis, the bicyclic aldehyde was masked as the acetal, and an efficient Fischer indole synthesis was performed using phenylhydrazine hydrochloride along with 4% H2SO4. Several subsequent steps led to the natural product. 

Cook et al. accomplished the enantiospecific total synthesis of the indole alkaloid tryprostatin A. The substituted indole nucleus was assembled at the beginning of the synthesis, and the necessary arylhydrazone was prepared via the Japp-Kiingemann reaction using the diazonium salt derived from m-anisidine and the anion of ethyl-a-ethylacetoacetate. The regioselectivity of the Fischer indoie synthesis favored the 6-methoxy-3-methylindole-2-carboxylate regioisomer in a 10 1 ratio. 

Zeolites can promote the cyclisation of ketone phenylhydrazones [43]. The phenylhydrazones of acetone and cyclohexanone cyclise in good yields to methylindole and tetrahydrocarbazole, respectively, in the presence of CaX zeolite. Zeolite beta is a highly selective catalyst for the synthesis of 2-benzyl-3-methylindole from phenylhydrazine and l-phenyl-2-butanone (e.g. equation 4.5) [44]. Clays have been reported to promote the ring closure of phenylhydrazones in a similar way [45]. Montmorillonite clay catalyses the ring closure of iV-benzylidene anilines with vinyl ethers to yield tetrahydroquinolines and azetidine derivatives [46]. 

Of preparative importance is the substitution of chloride or bromide or iodide, since the more reactive alkyl iodides are better substrates for further transformations. Alkyl iodides often are difficult to prepare directly, which is why the conversion of readily accessible chlorides or bromides via a Finkelstein reaction is often preferred. 

Differences in solubility of the reactants may for example be utilized as follows. Sodium iodide is much more soluble in acetone than are sodium chloride or sodium bromide. Upon treatment of an alkyl chloride or bromide with sodium iodide in acetone, the newly formed sodium chloride or bromide precipitates from the solution and is thus removed from equilibrium. Alkyl iodides can be conveniently prepared in good yields by this route. Alkyl bromides are more reactive as the corresponding chlorides. Of high reactivity are a-halogen ketones, a-halogen carboxylic acids and their derivatives, as well as allyl and benzyl halides. 

Secondary or tertiary alkyl halides are much less reactive. For example an alkyl dichloride with a primary and a secondary chloride substituent reacts selectively by exchange of the primary chloride. The reactivity with respect to the Finkelstein reaction is thus opposite to the reactivity for the hydrolysis of alkyl chlorides. For the Finkelstein reaction on secondary and tertiary substrates Lewis acids may be used, e.g. ZnCla, FeCls or MesAl. 

Alkyl fluorides can be prepared by the Finkelstein reaction. The fluoride anion is a bad leaving group the reverse reaction thus does not take place easily, and the equilibrium lies far to the right. As reagents potassium fluoride, silver fluoride or gaseous hydrogen fluoride may be used. 

Heating of an aryl hydrazone 1 in the presence of a catalyst leads to elimination of ammonia and formation of an indole 2. This reaction is known as the Fischer indole synthesisy and is somewhat related to the Benzidine rearrangement. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 98, Springer-Verlag Berlin Heidelberg 2009 

Borregan, M. Bradshaw, B. Vails, N. Bonjoch, J. Tetrahedron Asymmetry 2008,19, 2130-2134. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 106, Springer International Publishing Switzerland 2014 

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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 ... 

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. 

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. 

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)... 

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...

R] Robinson, B. The Fischer Indole Synthesis-, J. Wiley Sons New York, 1982 923pp. 

Isothiazolone dioxide rings are readily cleaved in diluted aqueous alkaline solution at r.t. and this feature allows their use, in some cases, as a protecting group (95TL(36)6227). An example is the efficient Fischer indole synthesis of 72. 

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