Indoles-preparation, Fischer synthesis

The Fischer synthesis is the condensation of an aryl hydrazine with a ketone followed by cyclisation of the resultant hydrazone under acidic conditions to give the corresponding indole, as illustrated by the preparation of 2-phenyl indole 7.9. 

In the Fischer synthesis, indoles are prepared from a ketone 40 and a phenylhydrazine derivative 41 (Eq. 15.4.3). The two-step-reaction, starting with a condensation towards a phenylhydrazone 42 and followed by an acid-catalyzed cyclisation with elimination of ammonia, is usually combined in a one-pot procedure (72). 

The Fischer indole synthesis is commonly recognized as one of the most powerful and versatile tools for construction of indoles, as reflected by the amount of recent publications in which it has been used successfully. The usual approach involves initial preparation of a phenylhydrazone 323 from a suitable phenylhydrazine and an enolizable carbonyl compound, followed by an acid-induced cyclization to the target indole 324, featuring a [3,3]-sigmatropic rearrangement as the key step (Scheme 38). Some selected new examples of indoles prepared using standard Fischer conditions are collected in Table 2. 

Using a-acetyl-y-butyrolactone as the carbonyl component in the Fischer synthesis, decarboxylation occurs and it is thus possible to prepare a 1,2-disub-stituted indol-3-ylethanol [2637]. In a related reaction, a y-haloaldehyde or a y-haloketone reacts with an arylhydrazine to give a tryptamine in which the side-chain nitrogen is derived from the terminal nitrogen of the reacting phenylhydrazine this and related reactions were reviewed in 1974 and 1988 [2641,3461). The course of Fischer indolization of the preformed monophenyl-hydrazone of cyclohexane-1,3-dione changes when the reaction is allowed to proceed under conditions which encourage ketal formation [2565]. 

When the Fischer synthesis is applied to an unsymmetrical ketone, either one of two isomers or a mixture of them may be produced. (+)-3-MethylcycIopen-tanone gives a mixture of I- and 2-methylcyclopent[0]indoles, and the relative amounts of these formed under various conditions are analysed [3222]. Further work has recently been published on the Fischer indolization of -methoxy-phenyl- -phenylhydrazones of an unsymmetrical ketone (ethyl pyruvate). Cyclization in acid occurs mostly on to the more electron-rich benzene ring whereas under nonacidic (for example, thermal) conditions there is less regio-selectivity [3539]. 2-Methoxyphenylhydrazine sometimes behaves anomalously and does not yield the expected 7-methoxyindole, but when o-4-toluenesuIphonyl-or o-4-trifluoromethylsulphonyI-phenylhydrazine is used to prepare the hydra-zone, the main product is the 7-sulphonyloxyindole which may be hydrolysed to the 7-hydroxyindole with alkali [3629]. 

The phenylhydrazones required for the Fischer synthesis are prepared from carbonyl compounds and phenylhydrazine. Alternatively, they can be obtained by a Japp-Klingemann reaction from CH-acidic compounds (y diketones, y -keto esters, etc.) or from enamines by interaction with aryldia-zonium salts. More complex indoles are thus accessible by a simple route. This is demonstrated by the synthesis of 3-(indol-3-yl)propionic acid 40, the starting material of Woodward s lysergic acid synthesis [52]. 

The total synthesis of aspidophytine (1) commenced with the preparation of the key tryptamine building block 9, as shown in Scheme 3. Although we have already confronted a typical means of indole preparation in Woodward s total synthesis of strychnine, namely the Fischer indole synthesis, in this context an alternative approach based on reductive cyclization was employed instead to fashion this heterocycle. Starting from known intermediate 14, ... 

The gem-dihalovinyl systems 100 can be convenientiy prepared from o-nitrobenzaldehydes 98 by Ramirez olefination (CBr4/PPh3) ( 99) followed by reduction of the NO2 group on catalytic hydrogenation with a V-doped Pt-C-catalyst. (9) Finally, some indole syntheses are available, which are (more or less) not deducible from retroanalytical considerations. To this category, above all, belongs the Fischer synthesis. 

The Fischer indole one-pot synthesis was also carried out using microwaves (Creencia et al, 2011). 1,2,3,4-tetrahydrocarbazole was obtained with good yield (76%), when a mixture of phenylhydrazine, cyclohexanone and zinc chloride was irradiated with microwaves (600 W) for 3 min. However, when zinc chloride was replaced with/ -toluenesulfonic acid (p-TSA), 1,2,3,4-tetrahydrocarbazole was produced with excellent yield (91%). Thus, a series of indoles were prepared using microwaves in the presence ofp-TSA catalyst. 

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 ... 

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... 

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)... 

Over 100 years after the initial discovery, the Fischer indole synthesis remains the most commonly employed method for the preparation of indoles. ... 

The Gassman indole synthesis provides a single regioisomer when ortho/para substituted anilines are employed, the yields of which are quite good generally. This provides some advantage in the preparation of 7-substituted indoles compared to other methods which normally give low yields, that is, the Fischer indole process. ... 

The Graebe-Ullman carbazole synthesis has been enmloyed in the preparation of substituted carbolines, as well as indolo[2,3-i] quinolines, which are often difficult to synthesize via other approaches, for example, the Fischer indole process. 

A synthesis of an indolo[3,2-fl]carbazole (2) was reported in 1951—the first preparation of a compound belonging to this class (Scheme 13). This was accomplished commencing with cyclohexanone, via conversion to the bishydrazone 108, which underwent Fischer indolization in glacial acetic acid to furnish the octahy-dro derivative 109. After a final dehydrogenation step, the desired product 2 was obtained (51JCS809). 

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 ... 

In addition to /3-diketones, /3-ketoacids and /3-ketoesters, cyanoacetic ester and related compounds are suitable starting materials. The arylhydrazones 4 thus obtained are of great importance as starting materials for the Fischer indole synthesis, as well as for the preparation of other iV-heterocycles. ... 

The classic and most convenient synthesis of the indole moiety is that of Emil Fischer. Recent examples of its use for drug synthesis includes one preparation of the nonsteroidal antiinflammatory agent, indoxole (2). Reaction of ketone 1 with phenylhydrazine in acetic acid leads directly to indoxole (2). Alternately, anisoin (3) can be reacted... 

A somewhat more complex example of the Fischer indole synthesis is provided by the tranquilizer, milipertine (8). It can be prepared by reaction of... 

Interestingly, the Fischer indole synthesis does not easily proceed from acetaldehyde to afford indole. Usually, indole-2-carboxylic acid is prepared from phenylhydrazine with a pyruvate ester followed by hydrolysis. Traditional methods for decarboxylation of indole-2-carboxylic acid to form indole are not environmentally benign. They include pyrolysis or heating with copper-bronze powder, copper(I) chloride, copper chromite, copper acetate or copper(II) oxide, in for example, heat-transfer oils, glycerol, quinoline or 2-benzylpyridine. Decomposition of the product during lengthy thermolysis or purification affects the yields. 

Indole-3-acetic acid has been prepared by the Fischer indole synthesis,2 by hydrolysis of indoleacetonitrile,3 from the reaction of gramine-type compounds with cyanide ion under conditions... 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

Moreover an equivalent of the Fischer indolization of hydrazones proved to be a versatile method of the pyrrolotropone and -tropolone synthesis. Hydrazones like 178a (prepared from 2-hydrazinotropones and carbonyl... 

Murakami et al. reported the total synthesis of 1-hydroxy-3-methylcarbazole (23) and murrayafoline A (7) by classical Fischer indolization of the O-methanesulfonyl phenylhydrazone derivative 614 (575). The compound 614 was prepared from the corresponding aminophenol 612 via 2-hydrazino-5-methylphenol p-toluenesulfonate... 

Mai et al. also reported a formal synthesis of murrayaquinone A (107) starting from murrayafoline A (7). However, the required murrayafoline A (7) was obtained by the benzannulation of furoindolone, which was prepared by Fischer indolization of 3-(2-phenylhydrazono)dihydrofuran-2(3H)-one (648) (see Scheme 5.46) (584) (Scheme 5.113). 

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