By the Fischer indole synthesis

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... 

A large number of carbazole syntheses have involved the preparation and dehydrogenation of hydrocarbazoles, mainly 1,2,3,4-tetrahydrocarbazoles, which are 2,3-disubstituted indoles. These, in turn, are usually prepared by the Fischer indole synthesis or the Bischler synthesis. This section will not deal with the preparation of the tetrahydrocarbazole, because... 

Other reactions of 2-vinylindoles with DMAD found in the literature are the reaction of A-benzyl-2-vinylindole, reported as a proof of structure of carbazoles obtained by the Fischer indole synthesis (82CJC419) the reaction of /3-aryl-2-vinylindoles, reported as a synthetic route to poten-... 

Figure 6.23 Formation of indoles from dissymmetric ketones by the Fischer indole synthesis.

The synthesis of dialkyl 3-aryl-2-indolylphosphonates 171 by the Fischer indole synthesis by the cycloaddition of arylhydrazines with a-ketophosphonates in polyphosphoric acid or under the influence of zinc chloride was described [183] ... 

Azoles can be produced from the products of palladium-catalyzed hydrazone arylation and can themselves serve as substrates for arylation reactions to produce N-aryl azoles by the Fischer indole synthesis. N-Aryl pyrazoles and related heterocycles can also be prepared after obtaining N-aryl hydrazines by palladium-catalyzed procedures. Benzophenone hydrazone was first found by both the Yale and MIT groups to be a particularly effective substrate for palladium-catalyzed reactions, as summarized in Eq. (25) [183, 184]. Reactions of benzophenone hydrazone with either aryl bromides or iodides occur in high yields in the presence of either DPPF- or BINAP-ligated palladium. These reactions are general and proceed with electron-rich, electron-poor, hindered, or unhindered aryl halides. The products of these re-... 

The synthesis of azaindoles by the Fischer indole synthesis has been tried more often than by any other method. It has given varied results, with over thirty successful ring closures of pyridyl- or quinolyl-hydrazones reported. Most of these have led to carboline deriva-... 

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

Acrolein can be used as starting material for tryptophan synthesis 227, 228, 239). The Michael-type condensation between acrolein (12) and ethyl acetamidomalonate (13) gives y-acetamido-y,y-dicarbethoxy-butyraldehyde (14), whose phenyhydrazone by the Fischer indole synthesis gives D,L-tryptophan. Of the hitherto reported methods, the synthetic route employed by Komachiya et al. 227) appears most suitable for the industrial synthesis of D,L-tryptophan. 

Maeda and Yoshida 238, 239) by hydroformylation of acrolein obtained l,l-diacetoxy-4,4-dialkoxybutane (17), which by Buecherer s reaction gave (3-(hydanto-5-yl-)propionaldehyde acetal (18). The phenyl-hydrazone of (18), by the Fischer indole synthesis, gave tryptophan hydantoin (20). Attempts to obtain crystalline (20) were unsuccessful,... 

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. 

Formation of a 1,2-disubstituted hydrazine by acid hydrolysis of an appropriately substituted pyrazolidine has been noted (67HC(22)l), but the most interesting ring fission of pyrazolidines involves the N(l)—N(2) bond of 1-phenylpyrazolidines (421). If, instead of phenylhydrazone, compound (421) is used in the Fischer indole synthesis, N- aminopropylin-doles are formed (73T4045). Scheme 39 shows the reaction with cyclohexanone. 

The Fischer indole synthesis can be regarded as the cyclization of an arylhydrazone 1 of an aldehyde or ketone by treatment with acid catalyst or effected thermally to form the indole nucleus 2. ... 

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

A microwave-assisted version of the Fischer indole synthesis was described by reaction of the hydrazone 179 [119]. The reaction was carried out on Mont-morillonite KIO doped with ZnCl2 giving reasonable yields of compound... 

In a process related to the Fischer indole synthesis, arenesulfinamides 96 underwent thermal conversion into the corresponding indoles 97 via a [3.3] sigmatropic rearrangement followed by cydization and loss of HSOH <96BSF329>. 

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

On the other hand, the nonbiogenetic approach usually adopts a convergent process such as shown in Scheme 15. When 18 is cleaved through C-6—C-7 (as 18 - 60), phenylhydrazine and a tricyclic moiety (61) which contains six chiral centers result. The synthetic problem then becomes synthesis of 61 followed by a Fischer indole synthesis and a final ring closure between C-6 and C-7 (61 -> 60 - 18). 

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence 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. 

The synthesis of cyclic ethers 137 was achieved by a Fischer indole synthesis starting from cyclic keto arylhydrazones generated in situ from 4-(hydroxy-methylene)-3,4-dihydrobenzo[ 7]oxepin-5(2H)-one 136 and the corresponding diazonium salt (Equation (20), 1993JHC1481). 

Iprindol (25) is yet another antidepressant drug that differs structurally from the classical tricyclic antidepressants. Condensation of phenylhydrazine and cyclooctanone by the Rogers-Corson modification of the Fischer indole synthesis affords the tricyclic intermediate, 24. The active hydrogen of 6,7,8,9,10-hexahydro-5H-cyclooct[b]indole (24) is removed by reaction with sodium metal in DMF and the resulting salt condensed with 3-dimethylaminopropyl chloride. There is thus obtained iprindol (25). ... 

A somewhat more complex example of the Fischer indole synthesis is provided by the tranquilizer. 

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