Fischer cyclization

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. 

The Fischer cyclization is usually carried out with a protic or Lewis acid which functions both to facilitate the formation of the cnchydrazine by tautomerization and also to assist the N N bond breakage. The mechanistic basis of the Fischer cyclization has been discussed in recent reviews[l,2]. 

The Fischer cyclization has proved to be a very versatile reaction which can tolerate a variety of substituents at the 2- and 3-positions and on the aromatic ring. An extensive review and compilation of examples was published several years ago[3]. From a practical point of view, the crucial reaction parameter is often the choice of the appropriate reaction medium. For hydrazones of unsymmetrical ketones, which can lead to two regioisomeric products, the choice of reaction conditions may determine the product composition. 

The mechanism of the Fischer cyclization outlined in equation 7.1 has been supported by spectroscopic observation of various intermediates[4] and by isolation of examples of intermediates in specialized structures[5]. In particular, it has been possible to isolate enehydrazines under neutral conditions and to demonstrate their conversion to indoles under the influence of acid cata-lysts[6]. 

Sigmatropic rearrangements are normally classified as concerted processes with relatively nonpolar transition states. However, the Fischer cyclization involves rearrangement of a charged intermediate and ring substituents have a significant effect on the rate of the rearrangement. The overall cyclization rate... 

The issue of regioselectivity arises with arylhydrazones of unsymmetrical ketones which can form two different enehydrazine intermediates. Under the conditions used most commonly for Fischer cyclizations, e g. ethanolic HCI, the major product is usually the one arising from the more highly substituted enehydrazine. Thus methyl ketones usually give 2-methy indoles and cycliz-ation occurs in a branched chain in preference to a straight chain. This regioselectivity is attributed to the greater stability of the more substituted enhydrazine and its dominance of the reaction path. 

Anomalous Fischer cyclizations are observed with certain c-substituted aryl-hydrazones, especially 2-alkoxy derivatives[l]. The products which are formed can generally be accounted for by an intermediate which w ould be formed by (ip50-substitution during the sigmatropic rearrangement step. Nucleophiles from the reaction medium, e.g. Cl or the solvent, are introduced at the 5-and/or 6-position of the indole ring. Even carbon nucleophiles, e.g. ethyl acetoacelate, can be incorporated if added to the reaction solution[2]. The use of 2-tosyloxy or 2-trifluoromethanesulfonyloxy derivatives has been found to avoid this complication and has proved useful in the preparation of 7-oxygen-ated indoles[3]. 

A special application of the Japp-Klingemann/Eischer sequence is in the preparation of tryptamines from piperidone-3-carboxylate salts, a method which was originally developed by Abramovitch and Shapiro[2]. When the piperidone is subjected to Japp-Klingemann coupling under mildly alkaline conditions decarboxylation occurs and a 3-hydrazonopiperidin-2-one is isolated. Fischer cyclization then gives 1-oxotetrahydro-p-carbolines which can be hydrolysed and decarboxylated to afford the desired tryptamine. 

Oxindoles can be prepared from Af,p-acylphenylhydrazines by a reaction which is analogous to the Fischer cyclization. This is known as the Brunner reaction. The reaction is typically conducted under strongly basic conditions. For example, heating Af-phenylcyclopentanecarbonylhydrazide with CaO gives a 70% yield of spiro-cyclopentane oxindole[l]. 

The oxygen analogue of the Fischer cyclization requires the formation of 0-vinyl derivatives of iV-arylhydroxylarnines. These are readily converted to indoles but are less readily accessible than the arylhydrazones used for the Fischer cyclization. 

The dialdehyde also underwent a Fischer cyclization with nitromethane and base to produce a mixture of four diasteriomeric nitropyranosides. The principal product was isolated by chromatography, hydrogenated usiag Raney nickel and then A/-acetylated to give... 

The quinolizine derivative 276 was obtained through a Friedel-Crafts acylation reaction onto the C-3 indole position of 275. This precursor was obtained by a sequence comprising a Fischer cyclization leading to 5-methyl-2-(2-pyridyl)indole 274, catalytic hydrogenation, N-alkylation with ethyl bromoacetate, and hydrolysis of the ester group (Scheme 59) <1999FA479>. 

SCHEME 40. Hale, Hough, and Richardson s studies on the reductive animation (1988) and Fischer cyclization (1987) of a 3, 4 -dialdehyde derived from lead tetraacetate oxidation of sucrose. The glycosyl morpholines were very sweet ... 

A. C. Richardson and H. O. L. Fischer, Cyclizations of dialdehydes with nitromethane, Part V. Preparation of some 3-amino-l,6-anhydro-3-deoxy-P-D-hexoses and the elucidation of their structures, Proc. Chem. Soc. (1960) 341-342. 

Three methods have thus emerged for the cyclization of dipeptide esters base-catalyzed cyclization (Fischer) cyclization without any added catalyst, under essentially neutral conditions (autoaminolysis Nitecki) and acetic acid-catalyzed cyclization (Suzuki). 

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... 

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). 

Almotriptan has also been synthesized via decarboxylation of the carboxylic acid intermediate 65, but a detailed preparation of 65 was not provided in the patent literature (Scheme 22)." The patent indicates that the carboxy indole 65 was prepared according to the method of Gonzalez.°° Thus, (2-oxo-tetrahydro-3-furanyl)-glyoxylic acid ethyl ester (62) was heated in aqueous H2SO4 to give 2-oxo-5-hydroxypentanoic acid in situ, which was treated with hydrazine 59 to produce hydrazone 63. Fischer cyclization of 63 using HCl gas in DMF gave the lactone 64, which was converted to carboxylic acid 65. Decarboxylation of 65 was catalyzed by cuprous oxide in quinoline at 190 °C to afford almotriptan (5)." ... 

A variety of both protic and Lewis acids have been used to effect Fischer cyclizations. Hydrochloric acid or sulfuric acid in aqueous, alcohol or acetic acid solution are frequently used. Polyphosphoric acid and BF3 in acetic acid have also been employed[10]. Zinc chloride is the most frequently used of the common Lewis acids. This choice is supported by comparative studies with FeCI3, AICI3, CoCI2 and NiCl2, which found ZnCl2 to be the most effective catalyst[l 1]. Zinc chloride can be used either as a solid mixture with the hydrazone reactant or in ethanol or acetic acid solution[12]. 

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