Fischer-indole reaction

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. 

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... 

Imitrex (Sumatriptan) 82 is the first selective 5-HTid agonist developed by Glaxo for the treatment of migraine. The synthesis of Imitrex has been carried out by several different routes all of which involved a Fischer indolization reaction as the key step. Outlined below is one of the synthetic routes. 

The reaction tolerates a variety of functional groups, especially the acid-sensitive acetal (81b), carbamate (81c) and the benzyl triazole (81d-f, and 81h, j). These intermediates, which are unstable under the conditions of the traditional Fischer indole reaction, were conveniently synthesized using this method. The structurally... 

Reaction of phenyldiazonium chloride with 66 provides 6-phenylhydrazono derivative 72. Fischer indolization reaction of 72 in polyphosphoric acid gives pentacyclic 3-azarutecarpine derivatives 73 (Equation 3) <1996T7789>. 

The required chirally substituted indoloazepine 219 was prepared by reaction of (5)-l-(l-naphthyl)ethylamine with the methiodide of 4-piper-idone (223), followed by a Fischer indole reaction leading to the V-carboline 224 (Scheme 56). Chlorination and reaction with thallium dimethylmalonate, followed by decarbomethoxylation of the resulting in-... 

Most indoles are synthesized by the Fischer indolization reaction. Here a phenylhydrazine is first reacted with an aldehyde, or ketone, carrying an a-methylene group (not acetaldehyde). The corresponding hydrazone is then treated with an acid, often hydrochloric acid. Ring closure occurs, through a [3,3]-sigmatropic change, and ammonia (as the ammonium cation) is lost (Scheme 7.14). 

An alternative synthesis from the Glaxo patents involves Fnedel-Crafts acylation of the 3-position of the indole intermediate 22 (Scheme 5) Reaction of hydrazine 10 with (phenylthio)acetaldehyde gave hydrazone 20, which was subjected to the Fischer indole reaction to give 3-thiophenylindole 21. It is noteworthy that this Fischer cyclization took place at room temperature because most require heat. Reductive desulfurization of 21 using Raney nickel provided indole 22. Acylation of the 3-position... 

The yield of the Fischer indole reaction was improved dramatically by employing 3-cyanopropanal diethylacetal as the aldehyde coupling partner (Scheme 10). Thus the hydrazone 33 was formed by reacting the hydrochloride salt of 31 with the diethylacetal in aqueous HCl. The hydrazone 33 was treated with polyphosphate ester in... 

Naratriptan was also prepared using the Fischer indole reaction (Scheme 15). Thus hydrazine 43 was condensed with Al-methyl-4-piperidineacetaldehyde in aqueous HCl to form hydrazone 44. Fischer indohzation was effected by treating 44 with polyphosphate ester in refluxing CHCI3 to provide naratriptan (3) in low yield. Higher yields may be attainable with the use of milder Fischer cyclization conditions (i.e. acetic acid or aqueous HCl). 

Scheme 15. Synthesis of naratriptan (3) using the Fischer indole reaction.

Scheme 21. Synthesis of almotriptan (5) using the Grandberg modification of the Fischer indole reaction.

Enamines derived from thiopyran-3-one, although tautomeric, tend to exist predominantly in conjugation with the sulfur atom the Fischer indole reaction, when applied to that ketone, affords solely the systems fused 2,3 on to the thiopyran (Scheme 10) (76CL5). 4-Amino-3,4-dihydro-2Ff-thiopyrans readily eliminate ammonia or amines on heating or treatment with acid, with formation of 2H- thiopyrans <78CR(C)(286)553). 

In this case, the Fischer indole reaction was catalysed by a Lewis acid, ZnCl2, and base-catalysed methylation followed. The final stages are summarized below. 

Treatment of a mixture of acetophenone phenylhydrazone and dimethyl acetylenedi-carboxylate with aluminium chloride gives the ene hydrazone 98, which undergoes a spontaneous Fischer indole reaction to yield the pyrrole 99 with elimination of aniline (equation 41)62. 

Factors Controlling the Regioselectivity in the Fischer Indole Synthesis The Fischer indole reaction has been extensively used for the synthesis of indole derivatives [77]. A problem is that two isomeric indoles are possible when the reaction is applied to arylhydrazones from dissymmetric methylene ketones, see Scheme 10. 

The selected items give a total of 600 possible combinations. Of these, 296 systems were studied in experimental runs, and of these, 162 afforded the Fischer indole reaction. The other systems failed. The successful systems were used for PLS modelling. The reaction were monitored by gas chromatography for 48 h after which time the increase in yield was insignificant. No isomerization occurred. The isomer distribution was determined from the gas chromatograms. The response used for PLS modelling was the regioisometrc excess, RE = Amount of major isomer — Amount of minor isomer. 

Table 16. Descriptors used for characterizing the reaction systems in the Fischer indole reaction...

The results obtained showed unequivocally that it is not possible to achieve a general control of the selectivity of the Fischer indole reaction in solution by the choice of certain combinations of Lewis acid catalysts and solvents. Previous claims in the literature are therefore not correct. It may well be that, for certain substrates, a proper combination of catalyst and solvent may enhance the selectivity, but this is not valid as a general principle. 

The same condensation-cyclization sequence with 4-methoxy-phenylhydrazine (292), however, proceeded in only 17% yield (113), so an alternative synthesis was devised for the important 8-oxygenated derivatives, such as 293 and 294, which employed a more conventional Fischer indole reaction (Scheme 47) (113). In the event, condensation of keto ketal 295 with hydrazine 280 gave hydrazone 296. Cyclization in hot diphenyl ether gave ketone 297, which, upon dehydrogenation, protection of the phenol as the benzoate, and chlorination gave 298. Deprotection and/or methylation afforded the target chloro-y-carbolines (299-301). 

Scheme 11. The Fischer Indole reaction of phenylhydrazine (I) with 3-heptanone (II) giving two indole products.

Now that we have got the hydrazone, the Fischer indole reaction is straightforward and gives i- indole-2-carboxylic acid derivative. There is only one site for the enamine, and the indole is forme away from the substituents already on the ring. 

Miller, B., Matjeka, E. R. The mechanism of 1,4-methyl migration is the Fischer Indole reaction. Tetrahedron Lett. 1977, 131-134. 

Douglas, A. W. In situ nitrogen-15 nuclear magnetic resonance observation of the Fischer indolization reaction. Nitrogen-15 NMR characterization of amide-imine intermediates. J. Am. Chem. Soc. 1979, 101, 5676-5678. 

Hughes, D. L. An unusual parabolic dependence of rate on acidity in the Fischer indole reaction. J. Phys. Org. Chem. 1994, 7, 625-628. 

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