Fischer synthesis of indoles

PPE is superior to PPA for the synthesis of 2-substituted benzimidazoles by the condensation of o-phenylenediamine with carboxylic acids. An aliphatic acid is heated with the amine and excess PPE at 100° for 10 min. (yields about 70%). Aromatic acids require a temperature of 120° and a reaction period of 20-40 min. (yields 50-60%). PPE has been used successfully in the Fischer synthesis of indoles from phenylhydrazones. ... 

Heterocycle formation (Hantzsch condensation, Pictet-Spengler, Fischer synthesis of indoles, Pd-heteroannulation)... 

Fischer indole synthesis. PPE is useful for Fischer synthesis of indoles from phenylhydrazones gentle refluxing for 5 minutes on a water bath generally completes the reaction.5 Thus cyclohexanone phenylhydrazone (1) under these conditions gives 1,2,3,4-tetrahydrocarbazole (2) in 86% yield. When the reaction mixture was heated to 160°, ethylation occured as well to give 3-ethyl-2,3-tetramethyleneindolenine (3) in fairly good yield. This alkylation reaction has... 

A useful alternative to the Fischer synthesis of indoles is that in which a primary arylamine is treated at — 70 C successively with t-butyl hypochlorite, methyl-... 

Because substituted anilines are widely available, they are ideal starting materials for the synthesis of indoles. Although anilines are often the precursors of the hydrazones used in the Fischer cyclization, more direct methods for conversion of anilines to indoles would be highly desirable. Such a process would, in general, have to involve some method for specific o -substitution of the aniline derivative. In the most successful method of this type which has been developed to date, a specific rearrangement effecting o-substitution is the key to a synthetic scheme which constructs indoles from anilines via anilinosulfonium ions. The procedure, which in appropriate circumstances can be carried out without isolation of the intermediates, involves oxidation of the aniline to an A-chloroaniline, reaction with a thiomethylmethyl ketone and a weak base, followed by cyclizative condensation (equation... 

The usual synthesis of indole derivative 1 is easy to attain by converting the key intermediate ketone 2 to compound 1 by Fischer indolization (Scheme 1). 

The synthesis of indoles by the Fischer method has been the subject of a review, where phosphorus trichloride and polyphosphoric acid were used as cyclizing agents [6], Although the first publication on the synthesis of phosphorus-containing indoles appeared in 1930 [7], reviews on this subject are few. The treatment of the subject in [8] was fragmentary, while the review [9] covered the literature up to 1975. It is also possible to mention [10], which was devoted to the phosphorylation of pyrrole and its carbonyl derivatives. 

The use of arylhydrazones for the synthesis of indoles has been widely discussed in the literature [1,2, 169], One of the most useable methods is the Fischer reaction [169, 170, 171], modified by Arbuzov [172],... 

Most recently, Wagaw, Yang, and Buchwald published a full account of the synthesis of indoles using the palladium-catalyzed amination process [185]. From the standpoint of catalysis, new results included improved turnover numbers and rates when Xantphos was used as ligand. Moreover, this ligand allowed diarylation of the hydrazone, including a one-pot sequential diarylation to provide mixed diaryl hydrazones. A procedure for the alkylation of N-aryl hydrazones was also reported. These procedures allow the formation of N-aryl and N-alkyl indoles after subjecting the products to Fischer conditions for indole synthesis. 

There is no need to restrict our discussion to carbon and oxygen atoms. We shall finish this section with two useful reactions that use other elements. The most famous synthesis of indoles is a nineteenth century reaction discovered by Emil Fischer—the Fischer indole synthesis—and it would be a remarkable discovery even today. Reaction of phenylhydrazine with a ketone in slightly acidic solution gives an imine (Chapter 14) called a phenylhydrazone. 

In the same domain of heterocyclic synthesis, much effort has been devoted to understanding the selectivities in the synthesis of indoles starting from phenylhydrazine and ketones, i.e. the Fischer indole synthesis. With phenyl-hydrazine, l-phenyl-2-butanone and zeolite H-Beta, the slimmer product 2-phenyl-3-methylindole dominates over the more bulky isomer (13) ... 

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. 

There has probably been more work carried out on the synthesis of indoles than on any other single heterocyclic system and consequently many routes are available ring syntheses of benzo[Z ]furans and benzo[fc]thiophenes have been much less studied. The Fischer indole synthesis, now more than 100 years old, is still widely used - an arylhydrazone is heated with an acid, a multi-step sequence ensues, ammonia is lost and an indole is formed. 

The Bischler-Napieralski (BN) method has demonstrated great utility for fully aromatic P-carboline rings. Substitution on carbocyclic ring A of the p-carboline system requires suitably substituted tryptamine which can be prepared via the Fischer indole synthesis or one of several methods for synthesis of indole rings (28, 128). 

Indoles are an important class of fine chemicals derivatives find application as fragrance chemicals. The indole nucleus is present in many biologically active molecules including plant-growth regulators, proteins and pharmaceuticals. The selective synthesis of indole derivatives constitutes an important area of drug research. The well-known Fischer indole synthesis provides a versatile method for synthesizing substituted indoles from the arylhydrazones of aldehydes or ketones... 

There are general reviews on heterocyclic syntheses by cycloaddition reactions of isocyanates and on the use of heterocyclic cations in preparative organic chemistry. More specific topics are 5-hydroxymethylfuran-2-carb-aldehyde, isobenzofurans and related ort/io-quinonoid systems, the conversion of 2//-cyclohepta[Zj] furan-2-one (1) into derivatives of azulene, the synthesis of indoles from o-alkylphenyl isocyanides, and abnormal Fischer indolization reactions of o-methoxyphenylhydrazones. Two reviews on isoindoles have appeared and a lecture on highly conducting charge-transfer complexes that are based on heterocyclic selenium and tellurium donors has been reprinted.Recent advances in the chemistry of imidazole and in the use of nitro-imidazoles as radiosensitizers have been summarized. There have been reviews on benzimidazole A -oxides and on dihydrobenzimidazoles, benzimidazolones, benzimidazolethiones, and related compounds. Other topics are synthetic applications of 1,3-dithiolium and 1,3-oxathiolium salts and of isoxazoles, the chemistry of benzisoxazoles, 2-amino-oxazoles, 5-oxazolones (2), furoxans, benzofuroxans, and related systems, the synthesis of five-membered meso-ionic compounds, and tetrazoles. ... 

The Japp-Klingemann reaction has been used extensively in the synthesis of indoles. 5-Methoxy-l//-indole-2-car boxy lie acid 25 has been prepared through a Japp-Klingemann-Fischer indole process in 81% overall yield from p-anisidine 21.10... 

As was mentioned before, isomerisation of the substituted indoles does not occur under the conditions used in this study. The selectivity of the catalytic reaction should therefore only depend on the relative rates of formation of the enehydrazines 2 and 3 in the conformation which aliows their [3,3]-sigmatropic rearrangement to occur (which is the conformation drawn in Scheme 1). The sorption data and molecular geometries indicate that the formation of both enehydrazines 2 and 3 inside the channels of zeolite beta should be possible, but 2 is probably severely hindered in adopting the conformation required for indolization, given the fact that this conformation is even bulkier than the indole isomer 4 which is formed from it. The selective Fischer synthesis of 2-benzyl-3-methylindole 5 catalyzed by zeolite beta is therefore a true example of transition state selectivity. 

The synthesis of indoles with this substitution pattern by the Fischer indole synthesis is described on p. 777. 

This reaction was first reported by Baeyer and Emmerling in 1869. It is the synthesis of indole via the alkaline reduction of o-nitro-cinnamic acid by iron. Although the Fischer Indole Synthesis has been considered as the most versatile approach for the indole derivatives, a few methods similar to Baeyer indole synthesis have also been developed so far. ... 

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. 

Several other newer indolization techniques completely unknown to Fischer and his contemporaries are cited here. The synthesis of indoles using continuous flow reactors has been described by the groups of Watts [79] and Cosford [80], The latter group synthesized a series of biologically active 2-(l/7-indol-3-yl)thiazoles 5 as shown in Scheme 6. 

As we will see in the Applications section to follow, solid-phase synthesis of indoles has assnmed an important role in all of synthetic organic chemistry, including Fischer... 

This final section on the Fischer indole ring synthesis discusses applications to the synthesis of indoles that were not included in the previous three sections. I have attempted to present mainly current examples of Fischer indolization. 

Scheme 15.106 One-pot synthesis of indoles by Zr-catalyzed hydrohydrazination/Fischer s indole synthesis without a second Lewis acid.

Fischer s interest in other heterocyclic molecules found in nature led to the first synthesis of caffeine, which is the stimulant in coffee and tea.The purine ring system found in caffeine also comprises the ring systems of the heterocyclic bases adenine and guanine that are found in nucleic acids. He also developed a general synthesis of indole, the heterocyclic ring-containing component in the amino acid tryptophan, and the method is known today as the Fischer indole synthesis. 

A synthesis of tryptophan (Trp, W) traditionally begins with the synthesis of the indole nucleus. Although a variety of pathways to variously substituted indole nuclei have been developed over the years (using the Fischer indole synthesis, Chapter 13) the simple unsubstituted system has generally proved more difficult than more highly substituted derivatives. Nonetheless, a decent synthesis of indole itself was worked out by A. Reissert and was reported as early as 1897. 

A new synthesis of indoles employs a rhodium-catalysed reaction between hydrazines and aldehydes or ketones. This process, therefore, is equivalent to the Fischer synthesis under non-acidic conditions. However, the yields in these reactions are not particularly high, and reaction temperatures of ca. 200 C are... 

A novel rhodium-catalyzed one-pot synthesis of indole systems via tandem hydroformylation-Fischer indole synthesis starting from olefins and arylhydrazines was described. The procedure leads directly to 3-substituted indoles if unsubstituted phenylhydrazine is used. Using para- or ortho-substituted arylhydrazines, the corresponding 3,5- and 3,7-disubstituted indoles are formed, respectively [160]. 

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... 

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