Indoles, synthesis Fischer

Construction of the indole ring via Fischer synthesis. Starting from a variety of 3,4-dihydro-lH-benzo[l ]azepine-2,5-diones 40 and arylhydrazines Fischer syntheses of indolo benzazepinones 41 have been reported (Scheme 8 (1999JMC2909)). Usually, the reaction comprises a two-step one-pot procedure with the formation of intermediate arylhydrazones in warm acetic acid followed... 

Two types of benzothiazepines with fused indole rings 301 and 302 (Figure 4) have been reported as products of a Fischer indole type synthesis (1993EJM659). 

As might be expected for a large branch of heterocyclic chemistry, many syntheses of indoles have been developed. We shall restrict our discussion to two, commencing with the widely-used 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. 

As shown in Equation (23), the condensation of w-diacetylbenzene with two equivalents of 8-hydrazinoquinoline gives the bis(pyrido[3,2-<7]indole) (48) in a Fischer synthesis upon cyclization of the intermediate bis(quinolinylhydrazone) with ppa (93JA872). 

In the second classical method (Bischler synthesis), an aromatic primary or secondary (arylalkyl, but not diaryl) amine is condensed with an obromo (or better, hydroxy) ketone to give a 2,3-dialkylindole. This in turn is alkylated directly to the 1,2,3,3-tetraalkylindoleninium salt. Use of acetoin gives 2,3-dimethylindole, which is easily isolated and purified. The Bischler synthesis from a substitued aniline, and especially from anilines bearing one or more alkoxy groups, is much preferred in practice for indoles substitued in the 4-7-positions, since the substituted aiylhy-drazines needed for the Fischer synthesis are costly, unstable, or unavailable. 

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). 

As shown in Equation 15.4.3, the use of non-symetrical ketones in the Fischer synthesis results in two isomeric indoles, 45 and 46. For some applications, it is advantageous to obtain a single isomer in high selectivity. 

It is also possible to use the Fischer synthesis for crafting indoles fused to other heterocyclic rings. This has been nicely demonstrated by initial formation of the enehydrazines 344, which were subsequently cyclized to the /3-carboline derivatives 345 (Scheme 42). An additional dehydrogenation step provided access to the corresponding... 

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-... 

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]. 

Inspection of Scheme 1 shows that the use of non-symmetrical ketones will result in two isomeric enehydrazine tautomers and hence in two isomeric indoles. When it is desired to obtain a single isomer, either a difficult separation procedure is required or, alternatively, the Fischer synthesis should be conducted with the... 

Product isomer distribution in the Fischer synthesis is determined by the complex interaction of several factors, so caution must be exercised in the attribution of changes in product-isomer distribution to specific causes such as shape selectivity. The principal factor determining the distribution of the indole isomers is the structure of the phenylhydrazone, as was shown by Prochazka and Carlson... 

Appreciable formation of the linear 2-benzyl-3-/f-indole by the Fischer synthesis with 1-phenyl-2-propanone was only observed with polyphosphoric acid and not at all with zeolite beta, although this product resembles, in bulkiness, 2-benzyl-3-methylindole, the linear indole isomer obtained from 1-phenyl-2-buta-none. If the production of the linear isomer depended solely on suppression of the formation of the bulky product, then the trends in the selectivities for 1-phenyl-... 

Modification for higher molecular indoles Comparison of steric hindrance on the Fischer indole ring synthesis and the Pfitzinger-Borsche quinoline ring synthesis s. 4, 843... 

PILLOTY ROBINSON Indole Synthesis Indole (caibazole) synthesis (ram azkws. see also Fischer. 

As is shown in Scheme 1, the use of non-symmetrical ketones in the Fischer synthesis will result in two isomeric indoles, 4 and 5. A detailed reaction mechanism is described in refs. [6] and [7], but some important characteristics will be given here. 

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