Systems 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). 

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...

In the section below, three examples are given of how the principles of factorial and fractional factorial designs can be applied in the selection of test systems. In the next chapter, an example is given of how a multi-level factorial design in the principal properties was used in conjunction with PLS modelling to analyze which properties of the reaction system are responsible for controlling the selectivity in the Fischer indole reaction. 

Five ketones, twelve Lewis acids and ten solvents were selected. These give a total of 600 different combinations. From these, 296 systems were selected and examined by experimental studies. The Fischer indole reaction was obtained with 162 of these systems. The PLS study was based on the 162 successful systems, in the hope that they would reveal a systematic pattern. A schematic illustration of the distribution of these systems in the reaction space is shown in Fig. 17.7. 

Table 17.9 Modelling power cf the variables in the PLS model of the Fischer indole reaction systems...

The table below specifies the reaction systems used in the study of the Fischer indole reaction. Reaction systems 1-124 were used to establish an initial PLS model. This model was validated by predictions of the remaining systems 125—162. The final model was then accomplished from all 162 reaction systems. The response given, RE, is the regioisomeric excess. 

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. ... 

Shortly thereafter, the first synthesis of the parent system 1 was reported, wherein Fischer indolization involving the carbazole derivative 12 furnished the desired product in 51% yield (Scheme 2). This achievement was correlated neatly with an alternative synthesis of 1 in 45% yield via the reaction of 1,2-cyclohexanedione mraiophenyUiydrazone and rtienylhydrazine in refluxing acetic acid, followed by treatment of the mixture with hot concentrated hydrochloric acid (57CIL363). 

The Fischer indole synthesis is of wide scope, and can be used for the preparation of substituted indoles and related systems. For example reaction of the phenylhydrazone 9, derived from cyclohexanone, yields the tetrahydrocar-bazole 10 ... 

Fischer indole synthesis Cyclization of arylhydrazones by heating with an acid or Lewis acid catalyst yields an indole system. The most commonly used catalyst is ZnCl2- The disadvantage of this reaction is that unsymmetrical ketones give mixtures of indoles if R also has an a-methylene group. 

Annelation of steroidal dienamines with substituted phenacyl bromides (7 examples) or with benzenediazonium salts (11 examples) has been shown to lead to the corresponding furano- and indolo-steroids.89 Thus the A3,5-dienamine derived from A4-androstene-3,17-dione reacted with p-bromophenacyl bromide to yield the A5-androstano[3,4-h]furan (199) in 26% yield, and reaction of the same A3,5-dienamine with benzenediazonium fluoroborate at -45 °C led to formation of the hydrazone (200) which underwent Fischer-indole cyclization on treatment with phosphorus oxychloride to produce the A4-androstano[6,7-6]indole (201). The A3,5-dienamine derived from 17/3-acetoxyandrost-4-en-3-one has been converted into the benz[4,5,6]-steroid (202 R1 = Me, R2 = H) by reaction with methyl vinyl ketone and into the analogous benzsteroid (202 R1 = H, R2 = Me) on treatment with crotonal-dehyde.90 A route to the condensed pyrroline ring system (203) has been devised... 

New approaches to the indole nucleus are continuously developed, providing aceess to indoles which are difficult to prepare using the well established reactions, such as the Fischer indole synthesis. Nevertheless, this classic reaction is still often used for constructing more complex systems, as exemplified by the preparation of 2-(pyrimidin-4-yl)indoles <03CPB975>, or indolo[3,2-i)]carbazoles possessing new substitution patterns <03T1265>. 

Bisagni and co-workers (113,116) also explored several synthetic routes to the tricyclic y-carbolines (5//-pyrido[4,3-i>]indole ring system). Unfortunately, the attractive one-step Nenitzescu reaction (114) proceeded in only 6% yield to afford 286 (113). The Fischer indolization sequence was far more efficient (Scheme 46) (113). Thus, condensation of phenylhydrazine with 279 in boiling diphenyl ether gave in one step the desired y-carboline 287 in excellent yield. Chlorination of the pyridone functionality gave chloropyridine 288, which was converted to the target amine-substituted y-carbolines 289—291 by heating with the appropriate amines. 

A new heterocyclic ring system, 5/-/,12/-/-[1]Benzoxepino[4,3-b]indol-6-one, was prepared by the Fischer indole cyciization of a substituted benzoxepin-5b-one phenylhydrazone by G. Primofiore and co-workers. The phenylhydrazone precursor was prepared via the Japp-Klingemann reaction of the corresponding 3,4-dihydro-4-hydroxymethylene[1]benzoxepin-5(2H)-one. 

The reaction space linked to the response space, illustrated by a study on the Fischer indole synthesis. The objective of the study was to determine which properties of the reaction system are necessary to control with a view to obtaining regioselectivity in the reaction. 

Properties of the reaction system related to the selectivity of a reaction. Regioselectivity in the Fischer indole synthesis.[ll]... 

This example describes how a PLS model can be used to identify those properties of a reaction system which determine the selectivity of a reaction. This technique has been apphed to the Fischer indole synthesis. A short description of the reaction is ... 

Table 17.8 Descriptors used to characterize the reaction systems in the study of the Fischer indole...

The PLS method is also the appropriate tool for determining which properties of the reaction system have an influence on the experimental results. An extensive study of the Fischer indole synthesis was given as an example. For analysis of this type of problem, an experimental design which affords a uniform spread in the principal properties should be used. 

Hydroamination reactions of alkynes provide an alternate route to arylhydrazones that can be utilized in the Fischer indole synthesis. Treatment of arylhydrazine 99 with alkyne 100 in the presence of catalyst system comprised of titanium tetrachloride and /-butylamine afforded arylhydrazone intermediate 101 which underwent a Fischer cyclization to give 1,2,3-trisubstituted indole 102 as a single regioisomer <04TL9541>. A similar titanium-catalyzed hydroamination reaction was utilized to prepare tryptamine derivatives <04TL3123>. 

Zeolites are known to catalyze the formation of various nitrogen-containing aromatic ring systems. Examples include the synthesis of pyridines by dehydrogenation / condensation / cyclization of C -Cg precursors [1], the formation of methylpyridines by high-temperature isomerization of anilines [2], the amination of oxygen-containing heterocyclic compounds [3] and the Fischer indole synthesis [4,5]. The latter synthesis consists (see Scheme 1) of a condensation towards a phenylhydrazone followed by an acid-catalyzed cyclization with elimination of ammonia. The two reaction steps are usually combined in a one-pot procedure. 

Gold-catalyzed addition of N-H and O-H to a triple bond has proven to be a rich source of protic acid-based multicatalytic systems. The setup for hydrogen transfer from Hantzsch esters has already been discussed other recent examples of Au/protic acid systems include combinations with well-known acid-catalyzed reactions such as the Fischer indole synthesis [114], Povarov reaction [115], and Diels-Alder reaction[116] (Scheme 26.26). 

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